Pyrazole compounds useful as protein kinase inhibitors

ABSTRACT

This invention describes novel pyrazole compounds of formula IIa:  
                 
 
     wherein R 1  is T-Ring D, wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R x  and R y  are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 heteroatoms; and R 2  and R 2  are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer&#39;s disease.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Pat. App.No. 60/257,887 filed Dec. 21, 2000 and U.S. Provisional Pat. App. No.60/286,949 filed Apr. 27, 2001, the contents of which are incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] The present invention is in the field of medicinal chemistry andrelates to compounds that are protein kinase inhibitors, compositionscontaining such compounds and methods of use. More particularly, thisinvention relates to compounds that are inhibitors of Aurora-2 proteinkinase. The invention also relates to methods of treating diseasesassociated with protein kinases, especially diseases associated withAurora-2, such as cancer.

BACKGROUND OF THE INVENTION

[0003] The search for new therapeutic agents has been greatly aided inrecent years by better understanding of the structure of enzymes andother biomolecules associated with target diseases. One important classof enzymes that has been the subject of extensive study is the proteinkinases.

[0004] Protein kinases mediate intracellular signal transduction. Theydo this by effecting a phosphoryl transfer from a nucleosidetriphosphate to a protein acceptor that is involved in a signalingpathway. There are a number of kinases and pathways through whichextracellular and other stimuli cause a variety of cellular responses tooccur inside the cell. Examples of such stimuli include environmentaland chemical stress signals (e.g. osmotic shock, heat shock, ultravioletradiation, bacterial endotoxin, H₂O₂), cytokines (e.g. interleukin-1(IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g.granulocyte macrophage-colony-stimulating factor (GM-CSF), andfibroblast growth factor (FGF). An extracellular stimulus may effect oneor more cellular responses related to cell growth, migration,differentiation, secretion of hormones, activation of transcriptionfactors, muscle contraction, glucose metabolism, control of proteinsynthesis and regulation of cell cycle.

[0005] Many diseases are associated with abnormal cellular responsestriggered by protein kinase-mediated events. These diseases includeautoimmune diseases, inflammatory diseases, neurological andneurodegenerative diseases, cancer, cardiovascular diseases, allergiesand asthma, Alzheimer's disease or hormone-related diseases.Accordingly, there has been a substantial effort in medicinal chemistryto find protein kinase inhibitors that are effective as therapeuticagents.

[0006] Aurora-2 is a serine/threonine protein kinase that has beenimplicated in human cancer, such as colon, breast and other solidtumors. This kinase is believed to be involved in proteinphosphorylation events that regulate the cell cycle. Specifically,Aurora-2 may play a role in controlling the accurate segregation ofchromosomes during mitosis. Misregulation of the cell cycle can lead tocellular proliferation and other abnormalities. In human colon cancertissue, the aurora-2 protein has been found to be overexpressed. SeeBischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J.Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997,272, 13766-13771.

[0007] Glycogen synthase kinase-3 (GSK-3) is a serine/threonine proteinkinase comprised of α and β isoforms that are each encoded by distinctgenes [Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim andKimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has beenimplicated in various diseases including diabetes, Alzheimer's disease,CNS disorders such as manic depressive disorder and neurodegenerativediseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; andHaq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be causedby, or result in, the abnormal operation of certain cell signalingpathways in which GSK-3 plays a role. GSK-3 has been found tophosphorylate and modulate the activity of a number of regulatoryproteins. These proteins include glycogen synthase which is the ratelimiting enzyme necessary for glycogen synthesis, the microtubuleassociated protein Tau, the gene transcription factor β-catenin, thetranslation initiation factor e1F2B, as well as ATP citrate lyase, axin,heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBα. These diverseprotein targets implicate GSK-3 in many aspects of cellular metabolism,proliferation, differentiation and development.

[0008] In a GSK-3 mediated pathway that is relevant for the treatment oftype II diabetes, insulin-induced signaling leads to cellular glucoseuptake and glycogen synthesis. Along this pathway, GSK-3 is a negativeregulator of the insulin-induced signal. Normally, the presence ofinsulin causes inhibition of GSK-3 mediated phosphorylation anddeactivation of glycogen synthase. The inhibition of GSK-3 leads toincreased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93,8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen,Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J.299, 123-128 (1994)]. However, in a diabetic patient where the insulinresponse is impaired, glycogen synthesis and glucose uptake fail toincrease despite the presence of relatively high blood levels ofinsulin. This leads to abnormally high blood levels of glucose withacute and long term effects that may ultimately result in cardiovasculardisease, renal failure and blindness. In such patients, the normalinsulin-induced inhibition of GSK-3 fails to occur. It has also beenreported that in patients with type II diabetes, GSK-3 is overexpressed[WO 00/38675]. Therapeutic inhibitors of GSK-3 therefore are consideredto be useful for treating diabetic patients suffering from an impairedresponse to insulin.

[0009] GSK-3 activity has also been associated with Alzheimer's disease.This disease is characterized by the well-known β-amyloid peptide andthe formation of intracellular neurofibrillary tangles. Theneurofibrillary tangles contain hyperphosphorylated Tau protein whereTau is phosphorylated on abnormal sites. GSK-3 has been shown tophosphorylate these abnormal sites in cell and animal models.Furthermore, inhibition of GSK-3 has been shown to preventhyperphosphorylation of Tau in cells [Lovestone et al., Current Biology4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)].Therefore, it is believed that GSK-3 activity may promote generation ofthe neurofibrillary tangles and the progression of Alzheimer's disease.

[0010] Another substrate of GSK-3 is β-catenin which is degradated afterphosphorylation by GSK-3. Reduced levels of β-catenin have been reportedin schizophrenic patients and have also been associated with otherdiseases related to increase in neuronal cell death [Zhong et al.,Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993);Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].

[0011] As a result of the biological importance of GSK-3, there iscurrent interest in therapeutically effective GSK-3 inhbitors. Smallmolecules that inhibit GSK-3 have recently been reported [WO 99/65897(Chiron) and WO 00/38675 (SmithKline Beecham)].

[0012] For many of the aforementioned diseases associated with abnormalGSK-3 activity, other protein kinases have also been targeted fortreating the same diseases. However, the various protein kinases oftenact through different biological pathways. For example, certainquinazoline derivatives have been reported recently as inhibitors of p38kinase (WO 00/12497 to Scios). The compounds are reported to be usefulfor treating conditions characterized by enhanced p38-a activity and/orenhanced TGF-β activity. While p38 activity has been implicated in awide variety of diseases, including diabetes, p38 kinase is not reportedto be a constituent of an insulin signaling pathway that regulatesglycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38inhibition would not be expected to enhance glycogen synthesis and/orglucose uptake.

[0013] There is a continued need to find new therapeutic agents to treathuman diseases. The protein kinases Aurora-2 and GSK-3 are especiallyattractive targets for the discovery of new therapeutics due to theirimportant roles in cancer and diabetes, respectively.

DESCRIPTION OF THE INVENTION

[0014] It has now been found that compounds of this invention andpharmaceutical compositions thereof are effective as protein kinaseinhibitors, particularly as inhibitors of Aurora-2. These compounds havethe general formula I:

[0015] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0016] Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein at leastone of Z¹ and Z² is nitrogen;

[0017] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³,or R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0018] Q is selected from —N(R⁴)—, —O—, —S—, —C(R^(6′))₂—,1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

[0019] R¹ is T-(Ring D);

[0020] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0021] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q is—C(R^(6′))₂—, a methylene unit of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—,—SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0022] Z is a C₁₋₄ alkylidene chain;

[0023] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶) CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N (R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶) —;

[0024] R² and R_(2′) are independently selected from —R, —T—W—R⁶, or R2and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² and R² isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴;

[0025] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic) , —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N (R⁷) CON (R⁷)₂, —N (R⁷)SO₂N(R⁷)₂, —N (R⁴)SO₂R,or —OC(═O)N(R⁷)₂;

[0026] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0027] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0028] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N (R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0029] V is —O—, —S—, —SO—, —SO2—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶) —,—CO—, —CO₂—, —N(R⁶)CO—, —N(R6)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶) —,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶) —, —C(R⁶)═N—O—,—C(R⁶)₂N (R⁶)N (R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

[0030] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶) OC(O) —, —C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶) CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0031] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom may be taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0032] each R^(6′) is independently selected from hydrogen or a C₁₋₄aliphatic group, or two R^(6′) on the same carbon atom are takentogether to form a 3-6 membered carbocyclic ring;

[0033] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0034] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N (R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N (R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0035] As used herein, the following definitions shall apply unlessotherwise indicated. The phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted” or withthe term “(un)substituted.” Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and each substitution is independent of the other.

[0036] The term “aliphatic” as used herein means straight-chain,branched or cyclic C₁-C₁₂ hydrocarbons which are completely saturated orwhich contain one or more units of unsaturation but which are notaromatic. For example, suitable aliphatic groups include substituted orunsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl. The terms “alkyl”, “alkoxy”, “hydroxyalkyl”,“alkoxyalkyl”, and “alkoxycarbonyl”, used alone or as part of a largermoiety includes both straight and branched chains containing one totwelve carbon atoms. The terms “alkenyl” and “alkynyl” used alone or aspart of a larger moiety shall include both straight and branched chainscontaining two to twelve carbon atoms. The term “cycloalkyl” used aloneor as part of a larger moiety shall include cyclic C₃-C₁₂ hydrocarbonswhich are completely saturated or which contain one or more units ofunsaturation, but which are not aromatic.

[0037] The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” meansalkyl, alkenyl or alkoxy, as the case may be, substituted with one ormore halogen atoms. The term “halogen” means F, Cl, Br, or I.

[0038] The term “heteroatom” means nitrogen, oxygen, or sulfur andincludes any oxidized form of nitrogen and sulfur, and the quaternizedform of any basic nitrogen. Also the term “nitrogen” includes asubstitutable nitrogen of a heterocyclic ring. As an example, in asaturated or partially unsaturated ring having 0-3 heteroatoms selectedfrom oxygen, sulfur or nitrogen, the nitrogen may be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

[0039] The terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic” as used herein means an aliphatic ring system having threeto fourteen members. The terms “carbocycle”, “carbocyclyl”,“carbocyclo”, or “carbocyclic” whether saturated or partiallyunsaturated, also refers to rings that are optionally substituted. Theterms “carbocycle”, “carbocyclyl”, “carbocyclo”, or “carbocyclic” alsoinclude aliphatic rings that are fused to one or more aromatic ornonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl,where the radical or point of attachment is on the aliphatic ring.

[0040] The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to aromatic ring groupshaving five to fourteen members, such as phenyl, benzyl, phenethyl,1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term “aryl”also refers to rings that are optionally substituted. The term “aryl”may be used interchangeably with the term “aryl ring”. “Aryl” alsoincludes fused polycyclic aromatic ring systems in which an aromaticring is fused to one or more rings. Examples include 1-naphthyl,2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scopeof the term “aryl”, as it is used herein, is a group in which anaromatic ring is fused to one or more non-aromatic rings, such as in anindanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical orpoint of attachment is on the aromatic ring.

[0041] The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as usedherein includes non-aromatic ring systems having five to fourteenmembers, preferably five to ten, in which one or more ring carbons,preferably one to four, are each replaced by a heteroatom such as N, O,or S. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one,(1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl,3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl,4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl,2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl,3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl,3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl,2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl,diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, andbenzothianyl. Also included within the scope of the term “heterocyclyl”or “heterocyclic”, as it is used herein, is a group in which anon-aromatic heteroatom-containing ring is fused to one or more aromaticor non-aromatic rings, such as in an indolinyl, chromanyl,phenanthridinyl, or tetrahydroquinolinyl, where the radical or point ofattachment is on the non-aromatic heteroatom-containing ring. The term“heterocycle”, “heterocyclyl”, or “heterocyclic” whether saturated orpartially unsaturated, also refers to rings that are optionallysubstituted.

[0042] The term “heteroaryl”, used alone or as part of a larger moietyas in “heteroaralkyl” or “heteroarylalkoxy”, refers to heteroaromaticring groups having five to fourteen members. Examples of heteroarylrings include 2-furanyl, 3-furanyl, 3-furazanyl, N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl,2-pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl,3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl,indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl,benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, orbenzoisoxazolyl. Also included within the scope of the term“heteroaryl”, as it is used herein, is a group in which a heteroatomicring is fused to one or more aromatic or nonaromatic rings where theradical or point of attachment is on the heteroaromatic ring. Examplesinclude tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[3,4-d]pyrimidinyl. The term “heteroaryl” also refers to ringsthat are optionally substituted. The term “heteroaryl” may be usedinterchangeably with the term “heteroaryl ring” or the term“heteroaromatic”.

[0043] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like)or heteroaryl (including heteroaralkyl and heteroarylalkoxy and thelike) group may contain one or more substituents. Examples of suitablesubstituents on the unsaturated carbon atom of an aryl, heteroaryl,aralkyl, or heteroaralkyl group include a halogen, —R°, —OR°, —SR°,1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy),phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), —CH₂ (Ph),substituted —CH₂ (Ph), —CH₂CH₂ (Ph), substituted —CH₂CH₂ (Ph), —NO₂,—CN, —N(R°)₂, —NR°C(O)R°, —NR°C(O)N(R°)₂, —NR°CO₂R°, —NR°NR°C(O)R°,—NR°NR°C(O)N(R°)₂, —NR°NR°CO₂R°, —C(O)C(O)R°, —C(O)CH₂C(O)R°, —CO₂R°,—C(O)R°, —C(O)N(R°)₂, —OC(O)N(R°)₂, —S(O)₂R°, —SO₂N(R°)₂, —S(O)R°,—NR°SO₂N(R°)₂, —NR°SO₂R°, —C(═S)N(R°)₂, —C(═NH)—N(R°)₂,—(CH₂)_(y)NHC(O)R°, —(CH₂)_(y)NHC(O)CH(V—R°) (R°); wherein each R° isindependently selected from hydrogen, a substituted or unsubstitutedaliphatic group, an unsubstituted heteroaryl or heterocyclic ring,phenyl (Ph), substituted Ph, —O(Ph), substituted —O(Ph), —CH₂(Ph), orsubstituted —CH₂(Ph); y is 0-6; and V is a linker group. Examples ofsubstituents on the aliphatic group or the phenyl ring of R° includeamino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy,dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl,alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

[0044] An aliphatic group or a non-aromatic heterocyclic ring maycontain one or more substituents. Examples of suitable substituents onthe saturated carbon of an aliphatic group or of a non-aromaticheterocyclic ring include those listed above for the unsaturated carbonof an aryl or heteroaryl group and the following: ═O, ═S, ═NNHR*,═NN(R*)₂, ═N—, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*,where each R* is independently selected from hydrogen, an unsubstitutedaliphatic group or a substituted aliphatic group. Examples ofsubstituents on the aliphatic group include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

[0045] Suitable substituents on the nitrogen of a non-aromaticheterocyclic ring include —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, and—NR⁺SO₂R⁺; wherein each R⁺ is independently selected from hydrogen, analiphatic group, a substituted aliphatic group, phenyl (Ph), substitutedPh, —O(Ph), substituted —O(Ph), CH₂(Ph), substituted CH₂(Ph), or anunsubstituted heteroaryl or heterocyclic ring. Examples of substituentson the aliphatic group or the phenyl ring include amino, alkylamino,dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy,haloalkoxy, or haloalkyl.

[0046] The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers are typically comprised of anatom such as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—,—C(O)NH—, or a chain of atoms, such as an alkylidene chain. Themolecular mass of a linker is typically in the range of about 14 to 200,preferably in the range of 14 to 96 with a length of up to about sixatoms. Examples of linkers include a saturated or unsaturated C₁₋₆alkylidene chain which is optionally substituted, and wherein one or twosaturated carbons of the chain are optionally replaced by —C(O)—,—C(O)C(O)—, —CONH—, —CONHNH—, —CO₂—, —OC(O)—, —NHCO₂—, —O—, —NHCONH—,—OC(O)NH—, —NHNH—, —NHCO—, —S—, —SO—, —SO₂—, —NH—, —SO₂NH—, or —NHSO₂—.

[0047] The term “alkylidene chain” refers to an optionally substituted,straight or branched carbon chain that may be fully saturated or haveone or more units of unsaturation. The optional substituents are asdescribed above for an aliphatic group.

[0048] A combination of substituents or variables is permissible only ifsuch a combination results in a stable or chemically feasible compound.A stable compound or chemically feasible compound is one in which thechemical structure is not substantially altered when kept at atemperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

[0049] Unless otherwise stated, structures depicted herein are alsomeant to include all stereochemical forms of the structure; i.e., the Rand S configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

[0050] Compounds of formula I or salts thereof may be formulated intocompositions. In a preferred embodiment, the composition is apharmaceutical composition. In one embodiment, the composition comprisesan amount of the protein kinase inhibitor effective to inhibit a proteinkinase, particularly Aurora-2, in a biological sample or in a patient.Compounds of this invention and pharmaceutical compositions thereof,which comprise an amount of the protein kinase inhibitor effective totreat or prevent an Aurora-2-mediated condition and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle, may be formulated foradministration to a patient.

[0051] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formula Ior a pharmaceutical composition thereof.

[0052] The term “Aurora-2-mediated disease” or “Aurora-2-mediatedcondition”, as used herein, means any disease or other deleteriouscondition in which Aurora is known to play a role. The terms“Aurora-2-mediated disease” or “Aurora-2-mediated condition” also meanthose diseases or conditions that are alleviated by treatment with anAurora-2 inhibitor. Such conditions include, without limitation, colon,breast, stomach, and ovarian cancer.

[0053] Another aspect of the invention relates to inhibiting Aurora-2activity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2 inhibitor of formula I, or acomposition thereof.

[0054] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0055] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0056] The terms “GSK-3-mediated disease” or “GSK-3-mediated condition”,as used herein, mean any disease or other deleterious condition or statein which GSK-3 is known to play a role. Such diseases or conditionsinclude, without limitation, diabetes, Alzheimer's disease, Huntington'sDisease, Parkinson's Disease, AIDS-associated dementia, amyotrophiclateral sclerosis (AML), multiple sclerosis (MS), schizophrenia,cardiomycete hypertrophy, reperfusion/ischemia, and baldness.

[0057] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0058] Another aspect of the invention relates to inhibiting GSK-3activity in a biological sample, which method comprises contacting thebiological sample with a GSK-3 inhibitor of formula I.

[0059] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0060] Another aspect of this invention relates to a method of treatingor preventing a CDK-2-mediated disease with a CDK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0061] The terms “CDK-2-mediated disease” or “CDK-2-mediated condition”,as used herein, mean any disease or other deleterious condition in whichCDK-2 is known to play a role. The terms “CDK-2-mediated disease” or“CDK-2-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with a CDK-2 inhibitor. Such conditionsinclude, without limitation, cancer, Alzheimer's disease, restenosis,angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes,psoriasis, atherosclerosis, alopecia, and autoimmune diseases such asrheumatoid arthritis. See Fischer, P. M. and Lane, D. P., CurrentMedicinal Chemistry, 7, 1213-1245 (2000); Mani, S., Wang, C., Wu, K.,Francis, R. and Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000);Fry, D. W. and Garrett, M. D., Current Opinion in Oncologic, Endocrine &Metabolic Investigational Drugs, 2, 40-59 (2000).

[0062] Another aspect of the invention relates to inhibiting CDK-2activity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0063] Another aspect of this invention relates to a method of treatingor preventing an ERK-2-mediated diseases with an ERK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0064] The terms “ERK-mediated disease” or “ERK-mediated condition”, asused herein mean any disease or other deleterious condition in which ERKis known to play a role. The terms “ERK-2-mediated disease” or“ERK-2-mediated condition” also mean those diseases or conditions thatare alleviated by treatment with a ERK-2 inhibitor. Such conditionsinclude, without limitation, cancer, stroke, diabetes, hepatomegaly,cardiovascular disease including cardiomegaly, Alzheimer's disease,cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis,restenosis, psoriasis, allergic disorders including asthma,inflammation, neurological disorders and hormone-related diseases. Theterm “cancer” includes, but is not limited to the following cancers:breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus,larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma,lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma,lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma,thyroid, follicular carcinoma, undifferentiated carcinoma, papillarycarcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, livercarcinoma and biliary passages, kidney carcinoma, myeloid disorders,lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx(oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum,large intestine, rectum, brain and central nervous system, and leukemia.ERK-2 protein kinase and its implication in various diseases has beendescribed [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al.,1990, Nature 343, 651; crews et al., 1992, Science 258, 478; Bjorbaek etal., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027;Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996;Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al.,1995, Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1993, Science260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al.,1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, Am. J. Respir.Cell Mol. Biol. 16, 589].

[0065] Another aspect of the invention relates to inhibiting ERK-2activity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0066] Another aspect of this invention relates to a method of treatingor preventing an AKT-mediated diseases with an AKT inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0067] The terms “AKT-mediated disease” or “AKT-mediated condition”, asused herein, mean any disease or other deleterious condition in whichAKT is known to play a role. The terms “AKT-mediated disease” or“AKT-mediated condition” also mean those diseases or conditions that arealleviated by treatment with a AKT inhibitor. AKT-mediated diseases orconditions include, but are not limited to, proliferative disorders,cancer, and neurodegenerative disorders. The association of AKT, alsoknown as protein kinase B, with various diseases has been described[Khwaja, A., Nature, pp. 33-34, 1990; Zang, Q. Y.; et al, Oncogene, 192000; Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000].

[0068] Another aspect of the invention relates to inhibiting AKTactivity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0069] Another aspect of this invention relates to a method of treatingor preventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0070] The terms “Src-mediated disease” or “Src-mediated condition”, asused herein mean any disease or other deleterious condition in which Srcis known to play a role. The terms “Src-mediated disease” or“Src-mediated condition” also mean those diseases or conditions that arealleviated by treatment with a Src inhibitor. Such conditions include,without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer,symptomatic treatment of bone metastasis, and Paget's disease. Srcprotein kinase and its implication in various diseases has beendescribed [Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64, 693(1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugsof the Future 2000, 25(7), 717, (2000); Talamonti, J. Clin. Invest., 91,53 (1993); Lutz, Biochem. Biophys. Res. 243, 503 (1998); Rosen, J. Biol.Chem., 261, 13754 (1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251(1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res.,76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. CancerRes., 5, 2164 (1999); Staley, Cell Growth Diff., 8, 269 (1997)].

[0071] Another aspect of the invention relates to inhibiting Srcactivity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0072] Another aspect of this invention relates to a method of treatingor preventing an Lck-mediated diseases with an Lck inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula I or apharmaceutical composition thereof.

[0073] The terms “Lck-mediated disease” or “Lck-mediated condition”, asused herein, mean any disease state or other deleterious condition inwhich Lck is known to play a role. The terms “Lck-mediated disease” or“Lck-mediated condition” also mean those diseases or conditions that arealleviated by treatment with an Lck inhibitor. Lck-mediated diseases orconditions include, but are not limited to, autoimmune diseases such astransplant rejection, allergies, rheumatoid arthritis, and leukemia. Theassociation of Lck with various diseases has been described [Molina etal., Nature, 357, 161 (1992)].

[0074] Another aspect of the invention relates to inhibiting Lckactivity in a biological sample or a patient, which method comprisesadministering to the patient a compound of formula I or a compositioncomprising said compound.

[0075] The term “pharmaceutically acceptable carrier, adjuvant, orvehicle” refers to a non-toxic carrier, adjuvant, or vehicle that may beadministered to a patient, together with a compound of this invention,and which does not destroy the pharmacological activity thereof.

[0076] The term “patient” includes human and veterinary subjects.

[0077] The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; preparations of an enzymesuitable for in vitro assay; biopsied material obtained from a mammal orextracts thereof; and blood, saliva, urine, feces, semen, tears, orother body fluids or extracts thereof.

[0078] An amount effective to inhibit protein kinase, for example,Aurora-2 and GSK-3, is an amount that causes measurable inhibition ofthe kinase activity when compared to the activity of the enzyme in theabsence of an inhibitor. Any method may be used to determine inhibition,such as, for example, the Biological Testing Examples described below.

[0079] Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions are generally known in the art. Theyinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

[0080] The compositions of the present invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously.

[0081] Sterile injectable forms of the compositions of this inventionmay be aqueous or oleaginous suspension. These suspensions may beformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed including synthetic mono-or di-glycerides. Fatty acids, such as oleic acid and its glyceridederivatives are useful in the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant,such as carboxymethyl cellulose or similar dispersing agents which arecommonly used in the formulation of pharmaceutically acceptable dosageforms including emulsions and suspensions. Other commonly usedsurfactants, such as Tweens, Spans and other emulsifying agents orbioavailability enhancers which are commonly used in the manufacture ofpharmaceutically acceptable solid, liquid, or other dosage forms mayalso be used for the purposes of formulation.

[0082] The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

[0083] Alternatively, the pharmaceutical compositions of this inventionmay be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient which is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

[0084] The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

[0085] Topical application for the lower intestinal tract can beeffected in a rectal suppository formulation (see above) or in asuitable enema formulation. Topically-transdermal patches may also beused.

[0086] For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

[0087] For ophthalmic use, the pharmaceutical compositions may beformulated as micronized suspensions in isotonic, pH adjusted sterilesaline, or, preferably, as solutions in isotonic, pH adjusted sterilesaline, either with or without a preservative such as benzylalkoniumchloride. Alternatively, for ophthalmic uses, the pharmaceuticalcompositions may be formulated in an ointment such as petrolatum.

[0088] The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

[0089] In addition to the compounds of this invention, pharmaceuticallyacceptable derivatives or prodrugs of the compounds of this inventionmay also be employed in compositions to treat or prevent theabove-identified diseases or disorders.

[0090] A “pharmaceutically acceptable derivative or prodrug” means anypharmaceutically acceptable salt, ester, salt of an ester or otherderivative of a compound of this invention which, upon administration toa recipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof. Particularly favored derivatives or prodrugs are thosethat increase the bioavailability of the compounds of this inventionwhen such compounds are administered to a patient (e.g., by allowing anorally administered compound to be more readily absorbed into the blood)or which enhance delivery of the parent compound to a biologicalcompartment (e.g., the brain or lymphatic system) relative to the parentspecies.

[0091] Pharmaceutically acceptable prodrugs of the compounds of thisinvention include, without limitation, the following derivatives of thepresent compounds: esters, amino acid esters, phosphate esters, metalsalts sulfonate esters, carbamates, and amides.

[0092] Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from pharmaceutically acceptableinorganic and organic acids and bases. Examples of suitable acid saltsinclude acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate,glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate,picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, tosylate and undecanoate. Other acids, such as oxalic,while not in themselves pharmaceutically acceptable, may be employed inthe preparation of salts useful as intermediates in obtaining thecompounds of the invention and their pharmaceutically acceptable acidaddition salts.

[0093] Salts derived from appropriate bases include alkali metal (e.g.,sodium and potassium), alkaline earth metal (e.g., magnesium), ammoniumand N⁺ (C₁₋₄ alkyl)₄ salts. This invention also envisions thequaternization of any basic nitrogen-containing groups of the compoundsdisclosed herein. Water or oil-soluble or dispersible products may beobtained by such quaternization.

[0094] The amount of the protein kinase inhibitor that may be combinedwith the carrier materials to produce a single dosage form will varydepending upon the patient treated and the particular mode ofadministration. Preferably, the compositions should be formulated sothat a dosage of between 0.01-100 mg/kg body weight/day of the inhibitorcan be administered to a patient receiving these compositions.

[0095] It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a varietyof-factors, including the activity of the specific compound employed,the age, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of the inhibitor will also depend upon the particular compound inthe composition.

[0096] Depending upon the particular protein kinase-mediated conditionto be treated or prevented, additional therapeutic agents, which arenormally administered to treat or prevent that condition, may beadministered together with the inhibitors of this invention. Forexample, in the treatment of cancer other chemotherapeutic agents orother anti-proliferative agents may be combined with the presentcompounds to treat cancer. These agents include, without limitation,adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil,topotecan, taxol, interferons, and platinum derivatives.

[0097] Other examples of agents the inhibitors of this invention mayalso be combined with include, without limitation, agents for treatingdiabetes such as insulin or insulin analogues, in injectable orinhalation form, glitazones, alpha glucosidase inhibitors, biguanides,insulin sensitizers, and sulfonyl ureas; anti-inflammatory agents suchas corticosteroids, TNF blockers, IL-1 RA, azathioprine,cyclophosphamide, and sulfasalazine; immunomodulatory andimmunosuppressive agents such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, interferons, corticosteroids, cyclophophamide,azathioprine, and sulfasalazine; neurotrophic factors such asacetylcholinesterase inhibitors, MAO inhibitors, interferons,anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonianagents; agents for treating cardiovascular disease such asbeta-blockers, ACE inhibitors, diuretics, nitrates, calcium channelblockers, and statins; agents for treating liver disease such ascorticosteroids, cholestyramine, interferons, and anti-viral agents;agents for treating blood disorders such as corticosteroids,anti-leukemic agents, and growth factors; and agents for treatingimmunodeficiency disorders such as gamma globulin.

[0098] Those additional agents may be administered separately from theprotein kinase inhibitor-containing composition, as part of a multipledosage regimen. Alternatively, those agents may be part of a singledosage form, mixed together with the protein kinase inhibitor of thisinvention in a single composition.

[0099] Compounds of this invention may exist in alternative tautomericforms, as in tautomers i and ii shown below. Unless otherwise indicated,the representation of either tautomer is meant to include the other.

[0100] R^(x) and R^(y) may be taken together to form a fused ring,providing a bicyclic ring system containing Ring A. PreferredR^(x)/R^(y) rings include a 5-, 6-, or 7-membered unsaturated orpartially unsaturated ring having 0-2 heteroatoms, wherein saidR^(x)/R^(y) ring is optionally substituted. Examples of bicyclic systemscontaining Ring A are shown below by compounds I-A through I-BB, whereinZ¹ is nitrogen or C(R⁸) and Z² is nitrogen or C(H).

[0101] Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D,I-E, I-F, I-I, I-J, I-K, I-P, I-Q, I-V, and I-U, more preferably I-A,I-B, I-D, I-E, I-J, I-P, and I-V, and most preferably I-A, I-B, I-D, I-Eand I-J.

[0102] In the monocyclic Ring A system, preferred R^(x) groups, whenpresent, include hydrogen, alkyl- or dialkylamino, acetamido, or a C₁₋₄aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.Preferred R^(y) groups, when present, include T-R³ or L-Z-R³ wherein Tis a valence bond or a methylene, L is —O—, —S—, —C(R⁶)₂O—, —CO— or—N(R⁴)—, and R³ is —R, —N(R⁴)₂, or —OR. Preferred R^(y) groups include5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl,4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl; C₁₋₆aliphatic, such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl;alkoxyalkylamino such as methoxyethylamino;, alkoxyalkyl such asmethoxymethyl or methoxyethyl; alkyl- or dialkylamino such as ethylaminoor dimethylamino; alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy; acetamido; and optionally substituted phenylsuch as phenyl or halo-substituted phenyl.

[0103] In the bicyclic Ring A system, the ring formed when R^(x) andR^(y) are taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC C(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.Preferred R^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0104] R² and R^(2′) may be taken together to form a fused ring, thusproviding a bicyclic ring system containing a pyrazole ring. Preferredfused rings include benzo, pyrido, pyrimido, and a partially unsaturated6-membered carbocyclo ring, wherein said fused ring is optionallysubstituted. These are exemplified in the following formula I compoundshaving a pyrazole-containing bicyclic ring system:

[0105] Preferred substituents on the R²/R^(2′) fused ring include one ormore of the following: —halo, —N(R⁴)₂, —C₁₋₃ alkyl, —C₁₋₃ haloalkyl,—NO₂, —O(C₁₋₃ alkyl), —CO₂(C₁₋₃ alkyl), —CN, —SO₂(C₁₋₃ alkyl), —SO₂NH₂,—OC(O)NH₂, —NH₂SO₂(C₁₋₃ alkyl), —NHC(O) (C₁₋₃ alkyl), —C(O)NH₂, and—CO(C₁₋₃ alkyl), wherein the (C₁₋₃ alkyl) is most preferably methyl.

[0106] When the pyrazole ring system is monocyclic, preferred R² groupsinclude hydrogen, C₁₋₄ aliphatic, alkoxycarbonyl, (un)substitutedphenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- ordialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of suchpreferred R² substituents include methyl, cyclopropyl, ethyl, isopropyl,propyl, t-butyl, cyclopentyl, phenyl, CO₂H, CO₂CH₃, CH₂OH, CH₂OCH₃,CH₂CH₂CH₂OH, CH₂CH₂CH₂OCH₃, CH₂CH₂CH₂OCH₂Ph, CH₂CH₂CH₂NH₂,CH₂CH₂CH₂NHCOOC(CH₃)₃, CONHCH(CH₃)₂, CONHCH₂CH═CH₂, CONHCH₂CH₂OCH₃,CONHCH₂Ph, CONH(cyclohexyl), CON(Et)₂, CON(CH₃)CH₂Ph, CONH(n-C₃H₇),CON(Et)CH₂CH₂CH₃, CONHCH₂CH(CH₃)₂, CON(n-C₃H₇)₂, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH₃,CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH₂CH₂OH, CONH₂, andCO(piperidin-1-yl). A preferred R^(2′) group is hydrogen.

[0107] An embodiment that is particularly useful for treatingAurora-2-mediated diseases relates to compounds of formula IIa:

[0108] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0109] R^(x) and R^(y) are taken together with their intervening atomsto form a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T-R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0110] R¹ is T-(Ring D);

[0111] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0112] T is a valence bond or a C₁₋₄ alkylidene chain;

[0113] Z is a C₁₋₄ alkylidene chain;

[0114] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N (R⁶) —,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)——C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶) —, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN (R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R₆)CON(R⁶)—;

[0115] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R_(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0116] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0117] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0118] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0119] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴) COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴) CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0120] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N (R⁶)—, —N—(R⁶) —,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R₆)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0121] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)—, —C(R₆)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0122] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0123] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0124] Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IIa are shownbelow.

[0125] More preferred pyrimidine ring systems of formula IIa includeIIa-A, IIa-B, IIa-D, IIa-E, IIa-J, IIa-P, and IIa-V, most preferablyIIa-A, IIa-B, IIa-D, IIa-E, and IIa-J.

[0126] The ring formed when R^(x) and R^(y) are taken together may besubstituted or unsubstituted. Suitable substituents include —R, halo,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR, —N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴) COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R⁴)₂, —N (R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂,wherein R and R⁴ are as defined above. Preferred R^(x)/R^(y) ringsubstituents include —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN,—O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R,—SO₂N(R⁴)₂ wherein R is hydrogen or an optionally substituted C₁₋₆aliphatic group.

[0127] The R² and R^(2′) groups of formula IIa may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIa compounds having apyrazole-containing bicyclic ring system:

[0128] Preferred substituents on the R²/R^(2′) fused ring of formula IIainclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl) , —CO₂ (C₁₋₄ alkyl), —CN, —SO₂ (C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl or ethyl.

[0129] When the pyrazole ring system of formula IIa is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, 1-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R_(2′) group is hydrogen.

[0130] When Ring D of formula IIa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0131] When Ring D of formula IIa is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0132] On Ring D of formula IIa, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0133] Preferred formula IIa compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0134] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a fused, unsaturated or partially unsaturated, 5-6membered ring having 0-2 heteroatoms selected from oxygen, sulfur, ornitrogen, wherein each substitutable ring carbon of said fused ringformed by R^(x) and R^(y) is independently substituted by oxo, T—R³, orL—Z—R³, and each substitutable ring nitrogen of said ring formed byR^(x) and R^(y) is independently substituted by R⁴;

[0135] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0136] (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

[0137] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R2′ aretaken together to form an optionally substituted benzo ring; and

[0138] (e) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

[0139] More preferred compounds of formula IIa have one or more, andmore preferably all, of the features selected from the group consistingof:

[0140] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

[0141] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selectedfrom an aryl or heteroaryl ring;

[0142] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0143] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0144] Even more preferred compounds of formula IIa have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0145] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

[0146] (b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring;

[0147] (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

[0148] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0149] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R)COCH₂N(R)₂, —N (R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0150] Representative compounds of formula IIa are shown below inTable 1. TABLE 1

IIa-1

IIa-2

IIa-3

IIa-4

IIa-5

IIa-6

IIa-7

IIa-8

IIa-9

IIa-10

IIa-11

IIa-12

IIa-13

IIa-14

IIa-15

IIa-16

IIa-17

IIa-18

IIa-19

IIa-20

IIa-21

IIa-22

IIa-23

IIa-24

IIa-25

IIa-26

IIa-27

IIa-28

IIa-29

IIa-30

IIa-31

IIa-32

IIa-33

IIa-34

IIa-35

IIa-36

IIa-37

IIa-38

IIa-39

IIa-40

IIa-41

IIa-42

IIa-43

IIa-44

IIa-45

IIa-46

IIa-47

IIa-48

IIa-49

IIa-50

IIa-51

IIa-52

IIa-53

IIa-54

IIa-55

IIa-56

IIa-57

IIa-58

IIa-59

IIa-60

IIa-61

IIa-62

IIa-63

IIa-64

IIa-65

IIa-66

IIa-67

IIa-68

IIa-69

IIa-70

IIa-71

IIa-72

IIa-73

IIa-74

IIa-75

IIa-76

IIa-77

IIa-78

IIa-79

[0151] In another embodiment, this invention provides a compositioncomprising a compound of formula IIa and a pharmaceutically acceptablecarrier.

[0152] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIa or a pharmaceutical composition thereof.

[0153] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIa or a compositioncomprising said compound.

[0154] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

[0155] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0156] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIa or a compositioncomprising said compound.

[0157] Another aspect of this invention relates to a method of treatingor preventing a CDK-2-mediated disease with a CDK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

[0158] Another aspect of the invention relates to inhibiting CDK-2activity in a patient, which method comprises administering to thepatient a compound of formula IIa or a composition comprising saidcompound.

[0159] Another aspect of this invention relates to a method of treatingor preventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIa or apharmaceutical composition thereof.

[0160] Another aspect of the invention relates to inhibiting Srcactivity in a patient, which method comprises administering to thepatient a compound of formula IIa or a composition comprising saidcompound.

[0161] Another method relates to inhibiting Aurora-2, GSK-3, CDK2, orSrc activity in a biological sample, which method comprises contactingthe biological sample with the Aurora-2, GSK-3, CDK2, or Src inhibitorof formula IIa, or a pharmaceutical composition thereof, in an amounteffective to inhibit Aurora-2, GSK-3, CDK2, or Src.

[0162] Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, CDK2, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIIa, as described above.

[0163] Another embodiment of this invention relates to compounds offormula IIb:

[0164] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0165] R^(x) and R^(y) are taken together with their intervening atomsto form a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0166] R¹ is T-(Ring D);

[0167] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0168] T is a valence bond or a C₁₋₄ alkylidene chain;

[0169] Z is a C₁₋₄ alkylidene chain;

[0170] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0171] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —ON, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0172] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0173] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0174] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0175] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0176] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0177] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0178] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0179] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0180] Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IIb are shownbelow.

[0181] More preferred pyrimidine ring systems of formula IIb includeIIb-A, IIb-B, IIb-D, IIb-E, IIb-J, IIb-P, and IIb-V, most preferablyIIb-A, IIb-B, IIb-D, IIb-E, and IIb-J.

[0182] The ring formed when R^(x) and R^(y) are taken together may besubstituted or unsubstituted. Suitable substituents include —R, halo,—O(CH₂)₂₋₄—N(R⁴)₂ , —O(CH₂)₂₋₄—R, —OR, —N (R⁴)—(CH₂)₂₋₄—N(R⁴)₂,—N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R,—SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁶)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂,—C═N—OR, —N(R⁴)CON(R ⁴)₂, —N(R⁴SO₂N(R⁴, —N(R⁴)SO₂R, or —OC(═O)N(R)₂, Rand R⁴ are as defined above. Preferred R^(x)/R^(y) ring substituentsinclude —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N (R⁴)₂,—O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R ishydrogen or an optionally substituted C₁₋₆ aliphatic group.

[0183] The R² and R^(2′) groups of formula IIb may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIb compounds having apyrazole-containing bicyclic ring system:

[0184] Preferred substituents on the R²/R^(2′) fused ring of formula IIbinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl or ethyl.

[0185] When the pyrazole ring system of formula IIb is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl, ,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0186] When Ring D of formula IIb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0187] When Ring D of formula IIb is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0188] On Ring D of formula IIb, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂ (n-propyl), —NHSO₂ (isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0189] Preferred formula IIb compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0190] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a fused, unsaturated or partially unsaturated, 5-6membered ring having 0-2 heteroatoms selected from oxygen, sulfur, ornitrogen, wherein each substitutable ring carbon of said fused ringformed by R^(x) and R^(y) is independently substituted by oxo, T—R³, orL—Z—R³, and each substitutable ring nitrogen of said ring formed byR^(x) and R^(y) is independently substituted by R⁴;

[0191] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0192] (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

[0193] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′)are taken together to form an optionally substituted benzo ring; and

[0194] (e) R³ is selected from —R, —halo, —OR, or —N(R⁴) ₂.

[0195] More preferred compounds of formula IIb have one or more, andmore preferably all, of the features selected from the group consistingof:

[0196] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

[0197] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selectedfrom an aryl or heteroaryl ring;

[0198] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0199] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0200] Even more preferred compounds of formula IIb have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0201] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

[0202] (b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring;

[0203] (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

[0204] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0205] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴) ₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N (R⁶) COCH₂N (R⁴)₂, —N (R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0206] Representative compounds of formula IIb are shown below in Table2. TABLE 2

IIb-1

IIb-2

IIb-3

IIb-4

IIb-5

IIb-6

IIb-7

IIb-8

IIb-9

[0207] In another embodiment, this invention provides a compositioncomprising a compound of formula IIb and a pharmaceutically acceptablecarrier.

[0208] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIb or a pharmaceutical composition thereof.

[0209] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIb or a compositioncomprising said compound.

[0210] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof.

[0211] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0212] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIb or a compositioncomprising said compound.

[0213] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0214] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIb, asdescribed above.

[0215] Another embodiment of this invention relates to compounds offormula IIc:

[0216] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0217] R^(x) and R^(y) are taken together with their intervening atomsto form a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0218] R¹ is T-(Ring D);

[0219] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0220] T is a valence bond or a C₁₋₄ alkylidene chain;

[0221] Z is a C₁₋₄ alkylidene chain;

[0222] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0223] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0224] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0225] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0226] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷;

[0227] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON (R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0228] V is —O—, —S—, —SO—, —SO₂, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C (R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0229] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0230] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0231] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0232] Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IIc are shownbelow.

[0233] More preferred pyrimidine ring systems of formula IIc includeIIc-A, IIc-B, IIc-D, IIc-E, IIc-J, IIc-P, and IIc-V, most preferablyIIc-A, IIC-B, IIc-D, IIC-E, and IIc-J.

[0234] The ring formed when R^(x) and R^(y) of formula IIc are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0235] The R² and R^(2′) groups of formula IIc may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIc compounds having apyrazole-containing bicyclic ring system:

[0236] Preferred substituents on the R²/R^(2′) fused ring of formula IIcinclude one or more of the following: is —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0237] When the pyrazole ring system of formula IIc is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl, ,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0238] When Ring D of formula IIc is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0239] When Ring D of formula IIc is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0240] On Ring D of formula IIc, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂ (n-propyl), —NHSO₂ (isopropyl), —NHCOEt, —NHCOCH₂NHCH₃, —NHCOCH₂N(CO₂t-Bu) CH₃, —NHCOCH₂N (CH₃)₂, —NHCOCH₂CH₂N (CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂ (morpholin-4-yl), —NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(Cl₄ aliphatic) such as —NHMe,—N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) such as —OMe,C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, ort-butyl, and CO₂(C₁₋₄, aliphatic).

[0241] Preferred formula IIc compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0242] (a) R^(x) and R^(y) are taken together with theirintervening-atoms to form a fused, unsaturated or partially unsaturated,5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur,or nitrogen, wherein each substitutable ring carbon of said fused ringformed by R^(x) and R^(y) is independently substituted by oxo, T—R³, orL—Z—R³, and each substitutable ring nitrogen of said ring formed byR^(x) and R^(y) is independently substituted by R⁴;

[0243] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0244] (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

[0245] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′)are taken together to form an optionally substituted benzo ring; and

[0246] (e) —R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

[0247] More preferred compounds of formula IIc have one or more, andmore preferably all, of the features selected from the group consistingof:

[0248] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

[0249] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selectedfrom an aryl or heteroaryl ring;

[0250] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0251] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0252] Even more preferred compounds of formula IIc have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0253] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

[0254] (b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring;

[0255] (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

[0256] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0257] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0258] Preferred compounds of formula IIc include compounds of formulaIIc:

[0259] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0260] R^(x) and R^(y) are taken together with their intervening atomsto form a fused benzo ring, wherein each substitutable ring carbon ofsaid fused ring formed by R^(x) and R^(y) is independently substitutedby T—R³, or L—Z—R³;

[0261] R¹ is T-(Ring D);

[0262] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0263] T is a valence bond or a C₁₋₄ alkylidene chain;

[0264] Z is a C₁₋₄ alkylidene chain;

[0265] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0266] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0267] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷) —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic), —N((R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

[0268] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0269] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0270] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0271] V is ——, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶))N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0272] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C (R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0273] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0274] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0275] The ring formed when R^(x) and R^(y) of formula IIc′ are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.Preferred R^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂, wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0276] The R2 and R^(2′) groups of formula IIc′ may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIc′ compounds having apyrazole-containing bicyclic ring system:

[0277] Preferred substituents on the R²/R^(2′) fused ring of formulaIIc′ include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl) , —CO₂(C₁₋₄ alkyl) , —CN,—SO₂(C₁₋₄ alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄alkyl), —C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is astraight, branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl)group is methyl.

[0278] When the pyrazole ring system of formula IIc′ is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0279] When Ring D of formula IIc′ is monocyclic, preferred Ring Dgroups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0280] When Ring D of formula IIc′ is bicyclic, preferred bicyclic RingD groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0281] On Ring D of formula IIc′, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂ (n-propyl), —NHSO₂ (isopropyl), —NHCOEt, —NHCOCH₂NHCH₃, —NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl), —NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂ (morpholin-4-yl), —NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic) such as —NHMe,—N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) such as —OMe,C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, ort-butyl, and —CO₂(C₁₋₄ aliphatic).

[0282] Preferred formula IIc′ compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0283] (a) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0284] (b) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

[0285] (c) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′)are taken together to form an optionally substituted benzo ring; and

[0286] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

[0287] More preferred compounds of formula IIc′ have one or more, andmore preferably all, of the features selected from the group consistingof:

[0288] (a) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selectedfrom an aryl or heteroaryl ring;

[0289] (b) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0290] (c) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0291] Even more preferred compounds of formula IIc′ have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0292] (a) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring;

[0293] (b) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

[0294] (c) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0295] (d) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0296] Other preferred compounds of formula IIc include compounds offormula IIc″:

[0297] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0298] R^(x) and R^(y) are taken together with their intervening atomsto form a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is optionally substituted by oxo, T—R³, or L—Z—R³, andeach substitutable ring nitrogen of said ring formed by R^(x) and R^(y)is optionally substituted by R⁴; provided that said fused ring formed byR^(x) and R^(y) is other than benzo;

[0299] R¹ is T-(Ring D);

[0300] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0301] T is a valence bond or a C₁₋₄ alkylidene chain;

[0302] Z is a C₁₋₄ alkylidene chain;

[0303] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶ )SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0304] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0305] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C—NN(R⁶)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0306] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0307] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0308] each R⁵ is independently selected from —R, halo, —OR, —C((═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0309] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0310] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)— or —CON(R⁶)—;

[0311] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0312] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0313] Preferred rings formed by R^(x) and R^(y) of formula IIc″ includea 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having1-2 heteroatoms, or a partially unsaturated carbocyclo ring, whereinsaid R^(x)/R^(y) ring is optionally substituted. This provides abicyclic ring system containing a pyrimidine ring. Examples of preferredpyrimidine ring systems of formula IIc″ are shown below.

[0314] More preferred pyrimidine ring systems of formula IIc″ includeIIc″-B, IIC-D, IIc-E, IIC-J, IIc-P, and IIc-V, most preferably IIC-B,IIC-D, IIC-E, and IIc-J.

[0315] The ring formed when R^(x) and R^(y) of formula IIc″ are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, wherein R and R⁴ are as defined above.Preferred R^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR,—CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0316] The R² and R^(2″) groups of formula IIc″ may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIc″ compounds having apyrazole-containing bicyclic ring system:

[0317] Preferred substituents on the R²/R^(2′) fused ring of formulaIIc″ include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0318] When the pyrazole ring system of formula IIc″ is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0319] When Ring D of formula IIc″ is monocyclic, preferred Ring Dgroups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0320] When Ring D of formula IIc″ is bicyclic, preferred bicyclic RingD groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0321] On Ring D of formula IIc″, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂—(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0322] Preferred formula IIc″ compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0323] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a fused, unsaturated or partially unsaturated, 5-6membered ring having 1-2 heteroatoms selected from oxygen, sulfur, ornitrogen, or a partially unsaturated 6-membered carbocyclo ring, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

[0324] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit, and Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring;

[0325] (c) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R^(2′)are taken together to form an optionally substituted benzo ring; and

[0326] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

[0327] More preferred compounds of formula IIc″ have one or more, andmore preferably all, of the features selected from the group consistingof:

[0328] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0329] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selectedfrom an aryl or heteroaryl ring;

[0330] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0331] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R)—.

[0332] Even more preferred compounds of formula IIc″ have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0333] (a) R^(x) and R^(y) are taken together to form a pyrido,piperidino, or cyclohexo ring, wherein each substitutable ring carbon ofsaid fused ring formed by R^(x) and R^(y) is independently substitutedby oxo, T—R³, or L—Z—R³, and each substitutable ring nitrogen of saidring formed by R^(x) and R^(y) is independently substituted by R⁴;

[0334] (b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring;

[0335] (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

[0336] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0337] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂ wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0338] Representative compounds of formula IIc are shown below in Table3. TABLE 3

IIc-1

IIc-2

IIc-3

IIc-4

IIc-5

IIc-6

IIc-7

IIc-8

IIc-9

IIc-10

IIc-11

IIc-12

IIc-13

IIc-14

IIc-15

IIc-16

IIc-17

IIc-18

IIc-19

IIc-20

IIc-21

IIc-22

IIc-23

IIc-24

IIc-25

IIc-26

IIc-27

IIc-28

IIc-29

IIc-30

IIc-31

IIc-32

IIc-33

IIc-34

IIc-35

IIc-36

IIc-37

IIc-38

IIc-39

IIc-40

IIc-41

IIc-42

IIc-43

IIc-44

IIc-45

IIc-46

IIc-47

IIc-48

IIc-49

IIc-50

IIc-51

IIc-52

IIc-53

IIc-54

IIc-55

IIc-56

IIc-57

IIc-58

IIc-59

IIc-60

IIc-61

IIc-62

IIc-63

IIc-64

IIc-65

IIc-66

IIc-67

IIc-68

IIc-69

IIc-70

IIc-71

IIc-72

IIc-73

IIc-74

IIc-75

IIc-76

IIc-77

IIc-78

IIc-79

IIc-80

IIc-81

IIc-82

IIc-83

IIc-84

IIc-85

IIc-86

IIc-87

IIc-88

IIc-89

IIc-90

[0339] In another embodiment, this invention provides a compositioncomprising a compound of formula IIc, IIc′, or IIc″, and apharmaceutically acceptable carrier.

[0340] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIc, IIc′, or IIc″, or a pharmaceutical composition thereof.

[0341] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIc, IIc′, or IIc″,or a composition comprising said compound.

[0342] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIc, IIc′,or IIc″, or a pharmaceutical composition thereof.

[0343] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIc, IIc′, orIIc″, or a pharmaceutical composition thereof. This method is especiallyuseful for diabetic patients. Another method relates to inhibiting theproduction of hyperphosphorylated Tau protein, which is useful inhalting or slowing the progression of Alzheimer's disease. Anothermethod relates to inhibiting the phosphorylation of β-catenin, which isuseful for treating schizophrenia.

[0344] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIc, IIc′, or IIc″,or a composition comprising said compound.

[0345] Another aspect of this invention relates to a method of treatingor preventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIc, IIc′, orIIc″, or a pharmaceutical composition thereof.

[0346] Another aspect of the invention relates to inhibiting Srcactivity in a patient, which method comprises administering to thepatient a compound of formula IIc, IIc′, or IIc″, or a compositioncomprising said compound.

[0347] Another aspect of this invention relates to a method of treatingor preventing an ERK-2-mediated diseases with an ERK-2 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIc, IIc′,or IIc″, or a pharmaceutical composition thereof.

[0348] Another aspect of the invention relates to inhibiting ERK-2activity in a patient, which method comprises administering to thepatient a compound of formula IIc, IIc′, or IIc″, or a compositioncomprising said compound.

[0349] Another aspect of this invention relates to a method of treatingor preventing an AKT-mediated diseases with an AKT inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIc, IIc′,or IIc″, or a pharmaceutical composition thereof.

[0350] Another aspect of the invention relates to inhibiting AKTactivity in a patient, which method comprises administering to thepatient a compound of formula IIc, IIc′, or IIc″, or a compositioncomprising said compound.

[0351] Another method relates to inhibiting Aurora-2, GSK-3, Src, ERK-2,or AKT activity in a biological sample, which method comprisescontacting the biological sample with the Aurora-2, GSK-3, Src, ERK-2,or AKT inhibitor of formula IIc, IIc′, or IIc″, or a pharmaceuticalcomposition thereof, in an amount effective to inhibit Aurora-2, GSK-3,Src, ERK-2, or AKT.

[0352] Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, Src, ERK-2, or AKT, or the treatment of a diseasealleviated thereby, is preferably carried out with a preferred compoundof formula IIc, IIc′, or IIc″, as described above.

[0353] Another embodiment that is particularly useful for treatingAurora-2-mediated diseases relates to compounds of formula IId:

[0354] or a pharmaceutically acceptable derivative or prodrug thereof,wherein;

[0355] Q′ is selected from —C(R^(6′))₂—, 1,2-cyclopropanediyl,1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

[0356] R^(x) and R^(y) are taken together with their intervening atomsto form a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R₄;

[0357] R¹ is T-(Ring D);

[0358] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0359] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q′is —C(R^(6′))₂— a methylene group of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—,—SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0360] Z is a C₁₋₄ alkylidene chain;

[0361] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0362] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0363] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)—₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0364] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0365] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —So₂R⁷;

[0366] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0367] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N (R⁶)CON(R⁶)—;

[0368] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0369] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0370] each R⁶ is independently selected from hydrogen or a C₁₋₄aliphatic group, or two R^(6′) on the same carbon atom are takentogether to form a 3-6 membered carbocyclic ring; and

[0371] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0372] Preferred rings formed by R^(x) and R^(y) include a 5-, 6-, or7-membered unsaturated or partially unsaturated ring having 0-2heteroatoms, wherein said R^(x)/R^(y) ring is optionally substituted.This provides a bicyclic ring system containing a pyrimidine ring.Examples of preferred pyrimidine ring systems of formula IId are shownbelow.

[0373] More preferred pyrimidine ring systems of formula IId includeIId-A, IId-B, IId-D, IId-E, IId-J, lId-P, and IId-V, most preferablyIId-A, IId-B, IId-D, IId-E, and IId-J.

[0374] The ring formed when R^(x) and R^(y) of formula IId are takentogether may be substituted or unsubstituted. Suitable substituentsinclude —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂ , —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0375] The R² and R^(2′) groups of formula lid may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IId compounds having apyrazole-containing bicyclic ring system:

[0376] Preferred substituents on the R²/R^(2′) fused ring of formula IIdinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0377] When the pyrazole ring system of formula IId is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0378] When Ring D of formula IId is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0379] When Ring D of formula lId is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0380] On Ring D of formula IId, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t-Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0381] Preferred Q′ groups of formula lId include —C(R^(6′))₂— or1,2-cyclopropanediyl, wherein each R^(6′) is independently selected fromhydrogen or methyl. A more preferred Q′ group is —CH₂—.

[0382] Preferred formula IIc compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0383] (a) R^(x) and R^(y) are taken together with their interveningatoms to form a fused, unsaturated or partially unsaturated, 5-6membered ring having 0-2 heteroatoms selected from oxygen, sulfur, ornitrogen, wherein each substitutable ring carbon of said fused ringformed by R^(x) and R^(y) is independently substituted by oxo, T—R³, orL—Z—R³, and each substitutable ring nitrogen of said ring formed byR^(x) and R^(y) is independently substituted by R⁴;

[0384] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit and wherein said methylene unit is optionally replaced by —O—,—NH—, or —S—;

[0385] (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 memberedbicyclic ring selected from an aryl or heteroaryl ring;

[0386] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; or R² and R_(2′)are taken together to form an optionally substituted benzo ring; and

[0387] (e) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.

[0388] More preferred compounds of formula IIc have one or more, andmore preferably all, of the features selected from the group consistingof:

[0389] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

[0390] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit and wherein said methylene unit is optionally replaced by —O—, andRing D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclicring selected from an aryl or heteroaryl ring;

[0391] (c) R² is —R and R_(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;

[0392] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—; and

[0393] (e) Q′ is —C(R⁶)₂— or 1,2-cyclopropanediyl, wherein each R^(6′)is independently selected from hydrogen or methyl.

[0394] Even more preferred compounds of formula IIc have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0395] (a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring;

[0396] (b) R¹ is T-Ring D, wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring;

[0397] (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen;

[0398] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl-,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—;

[0399] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring; and

[0400] (f) Q′ is —CH₂—.

[0401] Representative compounds of formula IId are shown below in Table4. TABLE 4

IId-1

IId-2

IId-3

IId-4

IId-5

IId-6

IId-7

IId-8

IId-9

IId-10

IId-11

IId-12

IId-13

IId-14

IId-15

IId-16

IId-17

IId-18

IId-19

[0402] In another embodiment, this invention provides a compositioncomprising a compound of formula IId and a pharmaceutically acceptablecarrier.

[0403] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIId or a pharmaceutical composition thereof.

[0404] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IId or a compositioncomprising said compound.

[0405] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IId or apharmaceutical composition thereof.

[0406] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IId or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0407] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IId or a compositioncomprising said compound.

[0408] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IId, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0409] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IId, asdescribed above.

[0410] Another embodiment of this invention relates to compounds offormula IIIa:

[0411] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0412] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

[0413] R¹ is T-(Ring D);

[0414] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0415] T is a valence bond or a C₁₋₄ alkylidene chain;

[0416] Z is a C₁₋₄ alkylidene chain;

[0417] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶) —, —C(R⁶)═N—O—,—C(R⁶)₂N (R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0418] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0419] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC (═O)N(R⁷)₂;

[0420] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0421] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0422] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0423] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0424] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0425] each R⁶ is independently selected from hydrogen or an 10optionally substituted C₁₋₄ aliphatic group, or two R⁶ groups on thesame nitrogen atom are taken together with the nitrogen atom to form a5-6 membered heterocyclyl or heteroaryl ring; and

[0426] each R⁷ is independently selected from hydrogen or an isoptionally substituted C₁₋₆ aliphatic group, or two R⁷ on the samenitrogen are taken together with the nitrogen to form a 5-8 memberedheterocyclyl or heteroaryl ring.

[0427] Preferred R^(x) groups of formula IIIa include hydrogen, alkyl-or dialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0428] Preferred R^(y) groups of formula IIIa include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0429] The R² and R^(2′) groups of formula IIIa may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIIa compounds having apyrazole-containing bicyclic ring system:

[0430] Preferred substituents on the R²/R^(2′) fused ring of formulaIIIa include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C⁴ alkyl) , —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl),—C(O)NH₂, and —CO (C₁₋₄ alkyl) , wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0431] When the pyrazole ring system of formula IIIa is monocyclic,preferred R²groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl, ,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0432] When Ring D of formula IIa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0433] When Ring D of formula IIIa is bicyclic, preferred bicyclic RingD groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0434] On Ring D of formula IIIa, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂ (n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃, —NHCOCH₂N(CO₂t - Bu) CH₃, —NHCOCH₂N (CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl), —NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic) such as —NHMe,—N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) such as —OMe,C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, ort-butyl, and —CO₂(C₁₋₄ aliphatic).

[0435] Preferred formula IIIa compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0436] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group;

[0437] (b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or amethylene and R³ is —R, —N(R⁴)₂, or —OR;

[0438] (c) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0439] (d) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0440] (e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0441] More preferred compounds of formula IIIa have one or more, andmore preferably all, of the features selected from the group consistingof:

[0442] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl;

[0443] (b) R¹ is T-(Ring D), wherein T is a valence bond;

[0444] (c) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring;

[0445] (d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0446] (e) L is —O—, —S—, or —N(R⁴)—.

[0447] Even more preferred compounds of formula IIIa have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0448] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetimido;

[0449] (b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

[0450] (c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N (R⁴)₂; and

[0451] (d) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic, and L is —O—, —S—, or —NH—.

[0452] Representative compounds of formula IIIa are shown below in Table5. TABLE 5

IIIa-1

IIIa-2

IIIa-3

IIIa-4

IIIa-5

IIIa-6

IIIa-7

IIIa-8

IIIa-9

IIIa-10

IIIa-11

IIIa-12

IIIa-13

IIIa-14

IIIa-15

IIIa-16

IIIa-17

IIIa-18

IIIa-19

IIIa-20

IIIa-21

IIIa-22

IIIa-23

IIIa-24

IIIa-25

IIIa-26

IIIa-27

IIIa-28

IIIa-29

IIIa-30

IIIa-31

IIIa-32

IIIa-33

IIIa-34

IIIa-35

IIIa-36

IIIa-37

IIIa-38

IIIa-39

IIIa-40

IIIa-41

IIIa-42

IIIa-43

IIIa-44

IIIa-45

IIIa-46

IIIa-47

IIIa-48

IIIa-49

IIIa-50

IIIa-51

IIIa-52

IIIa-53

IIIa-54

IIIa-55

IIIa-56

IIIa-57

IIIa-58

IIIa-59

IIIa-60

IIIa-61

IIIa-62

IIIa-63

[0453] In another embodiment, this invention provides a compositioncomprising a compound of formula IIIa and a pharmaceutically acceptablecarrier.

[0454] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIIa or a pharmaceutical composition thereof.

[0455] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIIa or a compositioncomprising said compound.

[0456] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIIa or apharmaceutical composition thereof.

[0457] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIIa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0458] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIIa or a compositioncomprising said compound.

[0459] Another aspect of this invention relates to a method of treatingor preventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIa or apharmaceutical composition thereof.

[0460] Another aspect of the invention relates to inhibiting Srcactivity in a patient, which method comprises administering to thepatient a compound of formula IIIa or a composition comprising saidcompound.

[0461] Another method relates to inhibiting Aurora-2, GSK-3, or Srcactivity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2, GSK-3, or Src inhibitor of formulaIIIa, or a pharmaceutical composition thereof, in an amount effective toinhibit Aurora-2, GSK-3, or Src.

[0462] Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIIIa, as described above.

[0463] Another embodiment of this invention relates to compounds offormula IIIb:

[0464] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0465] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

[0466] R¹ is T-(Ring D);

[0467] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0468] T is a valence bond or a C₁₋₄ alkylidene chain;

[0469] Z is a C₁₋₄ alkylidene chain;

[0470] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂-, —SO₂N(R6)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0471] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0472] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴)SO₂R, or—OC(═O)N(R⁷)₂;

[0473] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0474] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷;

[0475] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0476] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0477] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0478] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0479] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0480] Preferred R^(x) groups of formula IIIb include hydrogen, alkyl-or dialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0481] Preferred R^(y) groups of formula IIIb include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0482] The R² and R^(2′) groups of formula IIIb may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIIb compounds having apyrazole-containing bicyclic ring system:

[0483] Preferred substituents on the R²/R^(2′) fused ring of formulaIIIb include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0484] When the pyrazole ring system of formula IIIb is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0485] When Ring D of formula IIIb is monocyclic, preferred Ring Dgroups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0486] When Ring D of formula IIIb is bicyclic, preferred bicyclic RingD groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0487] On Ring D of formula IIIb, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCHCH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHS₂ (n-propyl), —NHSO₂ (isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0488] Preferred formula IIIb compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0489] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group;

[0490] (b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or amethylene and R³ is —R, —N(R⁴)₂, or —OR;

[0491] (c) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0492] (d) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0493] (e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0494] More preferred compounds of formula IIIb have one or more, andmore preferably all, of the features selected from the group consistingof:

[0495] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl;

[0496] (b) R¹ is T-(Ring D), wherein T is a valence bond;

[0497] (c) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring;

[0498] (d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, c₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0499] (e) L is —O—, —S—, or —N(R⁴)—.

[0500] Even more preferred compounds of formula IIIb have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0501] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetimido;

[0502] (b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

[0503] (c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂; and

[0504] (d) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic, and L is —O—, —S—, or —NH—.

[0505] Representative compounds of formula IIIb are shown below in Table6. TABLE 6

IIIb-1

IIIb-2

IIIb-3

IIIb-4

IIIb-5

IIIb-6

IIIb-7

IIIb-8

IIIb-9

IIIb-10

IIIb-11

IIIb-12

IIIb-13

IIIb-14

IIIb-15

IIIb-16

IIIb-17

IIIb-18

IIIb-19

IIIb-20

IIIb-21

IIIb-22

IIIb-23

IIIb-24

IIIb-25

IIIb-26

IIIb-27

IIIb-28

IIIb-29

IIIb-30

[0506] In another embodiment, this invention provides a compositioncomprising a compound of formula IIIb and a pharmaceutically acceptablecarrier.

[0507] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIIb or a pharmaceutical composition thereof.

[0508] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIIb or a compositioncomprising said compound.

[0509] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIIb or apharmaceutical composition thereof.

[0510] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIIb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0511] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIIb or a compositioncomprising said compound.

[0512] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIIb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0513] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIIb, asdescribed above.

[0514] Another embodiment of this invention relates to compounds offormula IIIc:

[0515] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0516] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

[0517] R¹ is T-(Ring D);

[0518] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0519] T is a valence bond or a C₁₋₄ alkylidene chain;

[0520] Z is a C₁₋₄ alkylidene chain;

[0521] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0522] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0523] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂,—C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂, —N(R⁴) SO₂R, or—OC(═O)N(R⁷)₂;

[0524] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0525] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0526] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0527] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O) N (R⁶)—, —OC(O) N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0528] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0529] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring; and

[0530] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0531] Preferred R^(x) groups of formula IIIc include hydrogen, alkyl-or dialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0532] Preferred R^(y) groups of formula IIIc include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R3 is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0533] The R² and R^(2′) groups of formula IIIc may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IIIc compounds having apyrazole-containing bicyclic ring system:

[0534] Preferred substituents on the R²/R^(2′) fused ring of formulaIIIc include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0535] When the pyrazole ring system of formula IIIc is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0536] When Ring D of formula IIIc is monocyclic, preferred Ring Dgroups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0537] When Ring D of formula IIIc is bicyclic, preferred bicyclic RingD groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0538] On Ring D of formula IIIc, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R )₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF³, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0539] Preferred formula IIIc compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0540] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group;

[0541] (b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or amethylene and R³ is —R, —N(R⁴)₂, or —OR;

[0542] (c) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0543] (d) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0544] (e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0545] More preferred compounds of formula IIIc have one or more, andmore preferably all, of the features selected from the group consistingof:

[0546] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from C₁₋₆ aliphatic, or 5-6 membered heterocyclyl, phenyl, or5-6 membered heteroaryl;

[0547] (b) R¹ is T-(Ring D), wherein T is a valence bond;

[0548] (c) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring;

[0549] (d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and

[0550] (e) L is —O—, —S—, or —N(R⁴)—.

[0551] Even more preferred compounds of formula IIIc have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0552] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetimido;

[0553] (b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

[0554] (c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂; and

[0555] (d) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic, and L is —O—, —S—, or —NH—.

[0556] Representative compounds of formula IIIc are shown below in Table7. TABLE 7

IIIc-1

IIIc-2

IIIc-3

IIIc-4

IIIc-5

IIIc-6

IIIc-7

IIIc-8

IIIc-9

IIIc-10

IIIc-11

IIIc-12

IIIc-13

IIIc-14

IIIc-15

IIIc-16

IIIc-17

IIIc-18

IIIc-19

IIIc-20

IIIc-21

IIIc-22

IIIc-23

IIIc-24

IIIc-25

IIIc-26

[0557] In another embodiment, this invention provides a compositioncomprising a compound of formula IIIc and a pharmaceutically acceptablecarrier.

[0558] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIc or a pharmaceutical composition thereof.

[0559] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIIc or a compositioncomprising said compound.

[0560] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIIc or apharmaceutical composition thereof.

[0561] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIIc or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0562] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIIc or a compositioncomprising said compound.

[0563] Another aspect of this invention relates to a method of treatingor preventing a Src-mediated disease with a Src inhibitor, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a compound of formula IIIc or apharmaceutical composition thereof.

[0564] Another aspect of the invention relates to inhibiting Srcactivity in a patient, which method comprises administering to thepatient a compound of formula IIIc or a composition comprising saidcompound.

[0565] Another method relates to inhibiting Aurora-2, GSK-3, or Srcactivity in a biological sample, which method comprises contacting thebiological sample with the Aurora-2, GSK-3, or Src inhibitor of formulaIIIc, or a pharmaceutical composition thereof, in an amount effective toAurora-2, GSK-3, or Src.

[0566] Each of the aforementioned methods directed to the inhibition ofAurora-2, GSK-3, or Src, or the treatment of a disease alleviatedthereby, is preferably carried out with a preferred compound of formulaIIIc, as described above.

[0567] Another embodiment of this invention relates to compounds offormula IIId:

[0568] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0569] Q′ is selected from —C(R^(6′))₂—, 1,2-cyclopropanediyl,1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;

[0570] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³;

[0571] R¹ is T-(Ring D);

[0572] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein each,substitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0573] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q′is —C(R^(6′))₂— a methylene group of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO2-,—SO2NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0574] Z is a C₁₋₄alkylidene chain;

[0575] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0576] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0577] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N (R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0578] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0579] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷;

[0580] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R₄)₂, —N(R⁴ )SO₂R, or —OC(═O)N(R⁴)₂;

[0581] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0582] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, C(R⁶)₂SO₂—,C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—CO₂—, —C(R⁶)OC(O)—, —C(R⁶)OC(O)N(R⁶)—,—C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)CON(R⁶)—, or—CON(R⁶)—;

[0583] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0584] each R^(6′) is independently selected from hydrogen or a C₁₋₄aliphatic group, or two R^(6′) on the same carbon atom are takentogether to form a 3-6 membered carbocyclic ring; and

[0585] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring.

[0586] Preferred R^(x) groups of formula IIId include hydrogen, alkyl-or dialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0587] Preferred R^(y) groups of formula IIId include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0588] The R² and R^(2′) groups of formula IIId may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IId compounds having apyrazole-containing bicyclic ring system:

[0589] Preferred substituents on the R²/R^(2′) fused ring of formulaIIId include one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl,—C₁₋₄ haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂ (C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄ alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄alkyl), —C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is astraight, branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl)group is methyl.

[0590] When the pyrazole ring system of formula IIId is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0591] When Ring D of formula IIId is monocyclic, preferred Ring Dgroups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0592] When Ring D of formula IIId is bicyclic, preferred bicyclic RingD groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0593] On Ring D of formula IIId, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N (CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0594] Preferred Q′ groups of formula IIId include —C(R⁶)₂— or1,2-cyclopropanediyl, wherein each R⁶ is independently selected fromhydrogen or methyl. A more preferred Q′ group is —CH₂—.

[0595] Preferred formula IIId compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0596] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group;

[0597] (b) R^(y) is T—R³ or L—Z—R³, wherein T is a valence bond or amethylene and R³ is —R, —N(R⁴)₂, or —OR;

[0598] (c) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit and wherein said methylene unit is optionally replaced by —O—,—NH—, or —S—;

[0599] (d) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0600] (e) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0601] More preferred compounds of formula IIId have one or more, andmore preferably all, of the features selected from the group consistingof:

[0602] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl;

[0603] (b) R¹ is T-(Ring D), wherein T is a valence bond;

[0604] (c) Ring D is a 5-6 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring;

[0605] (d) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered is heterocyclic ring;

[0606] (e) L is —O—, —S—, or —N(R⁴)—; and

[0607] (f) Q′ is —C(R^(6′))₂— or 1,2-cyclopropanediyl, wherein eachR^(6′) is independently selected from hydrogen or methyl.

[0608] Even more preferred compounds of formula IIId have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0609] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetimido;

[0610] (b) R^(y) is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- ordialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionallysubstituted phenyl, or methoxymethyl;

[0611] (c) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring, wherein Ring D is optionallysubstituted with one to two groups selected from —halo, —CN, —NO₂,—N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)SO₂R, —N(R⁶)COCH₂CH₂N(R⁴) ₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

[0612] (d) R² is hydrogen or a substituted or unsubstituted C₁₋₆aliphatic; and L is —O—, —S—, or —NH—; and

[0613] (e) Q′ is —CH₂—.

[0614] Representative compounds of formula IIId are shown below in Table8. TABLE 8

IIId-1

IIId-2

IIId-3

IIId-4

IIId-5

IIId-6

IIId-7

IIId-8

IIId-9

IIId-10

IIId-11

IIId-12

IIId-13

IIId-14

IIId-15

IIId-16

IIId-17

IIId-18

IIId-19

IIId-20

IIId-21

IIId-22

IIId-23

IIId-24

[0615] In another embodiment, this invention provides a compositioncomprising a compound of formula IIId and a pharmaceutically acceptablecarrier.

[0616] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIIId or a pharmaceutical composition thereof.

[0617] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IIId or a compositioncomprising said compound.

[0618] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IIId or apharmaceutical composition thereof.

[0619] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IIId or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0620] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IIId or a compositioncomprising said compound.

[0621] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IIId, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0622] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IIId, asdescribed above.

[0623] Another embodiment of this invention relates to compounds offormula IVa:

[0624] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0625] Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein one ofZ¹ or Z² is nitrogen;

[0626] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³,or R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0627] R¹ is T-(Ring D);

[0628] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0629] T is a valence bond or a C₁₋₄ alkylidene chain;

[0630] Z is a C₁₋₄ alkylidene chain;

[0631] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

[0632] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0633] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (C₁₋₆ aliphatic) ,—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0634] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0635] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON (R⁷)₂, or —SO₂R⁷;

[0636] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0637] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0638] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0639] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0640] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0641] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴) 2, —CON (R⁴) 2, —SO₂N (R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0642] Preferred rings formed by R^(x) and R^(y) of formula IVa includea 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having0-2 heteroatoms, wherein said R^(x)/R^(y) ring is optionallysubstituted. This provides a bicyclic ring system containing a pyridinering. Preferred pyridine ring systems of formula IVa are shown below.

[0643] More preferred pyridine ring systems of formula IVa includeIVa-A, IVa-B, IVa-D, IVa-E, IVa-J, IVa-P, and IVa-V, most preferablyIVa-A, IVa-B, IVa-D, IVa-E, and IVa-J. Even more preferred pyridine ringsystems of formula IVa are those described above, wherein Z′ is nitrogenand Z² is CH.

[0644] Preferred R^(x) groups of formula IVa include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0645] Preferred R^(y) groups of formula IVa include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0646] The ring formed when the R^(x) and R^(y) groups of formula IVaare taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O (CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N (R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR,—NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂ —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂, —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0647] The R² and R^(2′) groups of formula IVa may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IVa compounds having apyrazole-containing bicyclic ring system:

[0648] Preferred substituents on the R²/R^(2′) fused ring of formula IVainclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄alkyl) group ismethyl.

[0649] When the pyrazole ring system of formula IVa is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0650] When Ring D of formula IVa is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0651] When Ring D of formula IVa is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0652] On Ring D of formula IVa, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAC, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu) CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N (CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl), —NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl), —NHCOCH₂CH₂CH(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic) such as —NHMe,—N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) such as —OMe,C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, ort-butyl, and —CO₂(C₁₋₄ aliphatic).

[0653] Preferred R⁸ groups of formula IVa, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH2,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

[0654] Preferred formula IVa compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0655] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valencebond or a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-2heteroatoms selected from oxygen, sulfur, or nitrogen, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

[0656] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0657] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0658] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0659] More preferred compounds of formula IVa have one or more, andmore preferably all, of the features selected from the group consistingof:

[0660] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R— isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl; or R^(x) and R^(y) are takentogether with their intervening atoms to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0661] (b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D isa 5-6 membered monocyclic or an 8-10 membered bicyclic aryl orheteroaryl ring;

[0662] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;and

[0663] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0664] Even more preferred compounds of formula IVa have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0665] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetamido and R^(y) is selected from2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- ordialkylaminoalkoxy, acetamido, optionally substituted phenyl, ormethoxymethyl; or R^(x) and are taken together with their interveningatoms to form a benzo, pyrido, piperidino, or cyclohexo ring, whereinsaid ring is optionally substituted with —halo, —R, —OR, —COR, —CO₂R,—CON (R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂ —N(R⁴)₂, —NR⁴COR,—NR⁴SO₂R, or —SO₂N(R⁴)₂, wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group;

[0666] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring optionally substituted with one ortwo groups selected from —halo, —CN, —No₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂,—N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

[0667] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group, and R^(2′) ishydrogen; and

[0668] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L—is —O—, —S—, or —NH—; and

[0669] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0670] Representative compounds of formula IVa are shown below in Table9. TABLE 9

IVa-1

IVa-2

IVa-3

IVa-4

IVa-5

IVa-6

IVa-7

IVa-8

IVa-9

IVa-10

IVa-11

IVa-12

[0671] In another embodiment, this invention provides a compositioncomprising a compound of formula IVa and a pharmaceutically acceptablecarrier.

[0672] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVa or a pharmaceutical composition thereof.

[0673] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IVa or a compositioncomprising said compound.

[0674] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IVa or apharmaceutical composition thereof.

[0675] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVa or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0676] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IVa or a compositioncomprising said compound.

[0677] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IVa, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0678] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVa, asdescribed above.

[0679] Another embodiment of this invention relates to compounds offormula IVb:

[0680] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0681] Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein one ofZ¹ or Z² is nitrogen;

[0682] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³,or R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0683] R¹ is T-(Ring D);

[0684] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0685] T is a valence bond or a C₁₋₄ alkylidene chain;

[0686] Z is a C₁₋₄ alkylidene chain;

[0687] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)——C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0688] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0689] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0690] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0691] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0692] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0693] V is —O—, —S—, —SO, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—,—CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶) —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0694] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0695] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0696] each R₇ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0697] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic) ,—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0698] Preferred rings formed by R^(x) and R^(y) of formula IVb includea 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having0-2 heteroatoms, wherein said R^(x)/R^(y) ring is optionallysubstituted. This provides a bicyclic ring system containing apyrimidine is ring. Preferred pyrimidine ring systems of formula IVb areshown below.

[0699] More preferred pyrimidine ring systems of formula IVb includeIVb-A, IVb-B, IVb-D, IVb-E, IVb-J, IVb-P, and IVb-V, most preferablyIVb-A, IVb-B, IVb-D, IVb-E, and IVb-J. Even more preferred pyridine ringsystems of formula IVb are those described above, wherein Z¹ is nitrogenand Z² is CH.

[0700] Preferred R^(x) groups of formula IVb include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0701] Preferred R^(y) groups of formula IVb include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0702] The ring formed when the R^(x) and R^(y) groups of formula Ivbaare taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O (CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)_(2, —SO) ₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴ )CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0703] The R² and R^(2′) groups of formula IVb may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IVb compounds having apyrazole-containing bicyclic ring system:

[0704] Preferred substituents on the R²/R^(2′) fused ring of formula IVbinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄ alkyl), —CN, —SO₂(C₁₋₄alkyl), —SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O) (C₁₋₄ alkyl),—C(O)NH₂, and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight,branched, or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group ismethyl.

[0705] When the pyrazole ring system of formula IVb is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include hydrogen, methyl, ethyl,propyl, , cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,methoxypropyl, and benzyloxypropyl. A preferred R^(2′) group ishydrogen.

[0706] When Ring D of formula IVb is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0707] When Ring D of formula IVb is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0708] On Ring D of formula IVb, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAC, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃, —NHCOCH₂N(CO₂t -Bu) CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl), —NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0709] Preferred R⁸ groups of formula IVb, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

[0710] Preferred formula IVb compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0711] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valencebond or a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-2heteroatoms selected from oxygen, sulfur, or nitrogen, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

[0712] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0713] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0714] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0715] More preferred compounds of formula IVb have one or more, andmore preferably all, of the features selected from the group consistingof:

[0716] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl; or R^(x) and R^(y) are takentogether with their intervening atoms to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0717] (b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D isa 5-6 membered monocyclic or an 8-10 membered bicyclic aryl orheteroaryl ring;

[0718] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;and

[0719] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0720] Even more preferred compounds of formula IVb have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0721] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetamido and R^(y) is selected from2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- ordialkylaminoalkoxy, acetamido, optionally substituted phenyl, ormethoxymethyl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, piperidino, or cyclohexoring, wherein said ring is optionally substituted with —halo, —R, —OR,—COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂—N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or —SO₂N(R⁴)₂, wherein R is hydrogen or anoptionally substituted C₁₋₆ aliphatic group;

[0722] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring optionally substituted with one ortwo groups selected from —halo, —CN, —No₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂,—N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

[0723] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group, and R^(2′) ishydrogen; and (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0724] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —No₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0725] Representative compounds of formula IVb are shown below in Table10. TABLE 10

IVb-1

IVb-2

IVb-3

IVb-4

IVb-5

IVb-6

IVb-7

IVb-8

IVb-9

IVb-10

IVb-11

IVb-12

IVb-13

IVb-14

IVb-15

IVb-16

[0726] In another embodiment, this invention provides a compositioncomprising a compound of formula IVb and a pharmaceutically acceptablecarrier.

[0727] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVb or a pharmaceutical composition thereof.

[0728] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IVb or a compositioncomprising said compound.

[0729] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IVb or apharmaceutical composition thereof.

[0730] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVb or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0731] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IVb or a compositioncomprising said compound.

[0732] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IVb, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0733] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVb, asdescribed above.

[0734] Another embodiment of this invention relates to compounds offormula IVc:

[0735] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0736] Z¹ is nitrogen or C—R⁸ and Z² is nitrogen or CH, wherein one ofZ¹ or Z² is nitrogen;

[0737] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R³,or R^(x) and R^(y) are taken together with their intervening atoms toform a fused, unsaturated or partially unsaturated, 5-7 membered ringhaving 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0738] R¹ is T-(Ring D);

[0739] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0740] T is a valence bond or a C₁₋₄ alkylidene chain;

[0741] Z is a C₁₋₄ alkylidene chain;

[0742] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R)—;

[0743] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R2and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO2, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0744] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆ aliphatic) , —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0745] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0746] each R⁴ is independently selected from —R⁷, —COR⁷,—CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0747] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴) COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴) CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0748] V is —O—, —S—, —SO—, —SO₂O, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶) CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC (O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0749] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0750] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0751] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0752] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴) CON (R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0753] Preferred rings formed by R^(x) and R^(y) of formula IVc includea 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having0-2 heteroatoms, wherein said R^(x)/R^(y) ring is optionallysubstituted. This provides a bicyclic ring system containing a pyridinering. Preferred pyridine ring systems of formula IVc are shown below.

[0754] More preferred pyridine ring systems of formula IVc includeIVc-A, IVc-B, IVc-D, IVc-E, IVc-J, IVc-P, and IVc-V, most preferablyIVc-A, IVc-B, IVc-D, IVc-E, and IVc-J. Even more preferred pyridine ringsystems of formula IVc are those described above, wherein Z¹ is nitrogenand Z² is CH

[0755] Preferred R^(x) groups of formula IVc include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0756] Preferred R^(y) groups of formula IVc include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0757] The ring formed when the R^(x) and R^(y) groups of formula IVcare taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁶)CON(R⁶)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂, —NR⁴COR,—NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionally substitutedC₁₋₆ aliphatic group.

[0758] The R² and R^(2′) groups of formula IVc may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IVc compounds having apyrazole-containing bicyclic ring system:

[0759] Preferred substituents on the R²/R^(2′) fused ring of formula IVcinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched,or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

[0760] When the pyrazole ring system of formula IVc is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0761] When Ring D of formula IVc is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0762] When Ring D of formula IVc is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0763] On Ring D of formula IVc, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴) COR, —N(R⁴)CO₂R,—SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂(n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N (CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO (cyclopropyl), —NHCO (isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂(morpholin-4-yl),—NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic)such as —NHMe, —N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic)such as —OMe, C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl,isopropyl, or t-butyl, and —CO₂(C₁₋₄ aliphatic).

[0764] Preferred R⁸ groups of formula IVc, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O.

[0765] Preferred formula IVc compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0766] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valencebond or a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-2heteroatoms selected from oxygen, sulfur, or nitrogen, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

[0767] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit;

[0768] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0769] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R2′ aretaken together to form an optionally substituted benzo ring.

[0770] More preferred compounds of formula IVc have one or more, andmore preferably all, of the features selected from the group consistingof:

[0771] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl; or R^(x) and R^(y) are takentogether with their intervening atoms to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring,wherein each substitutable ring carbon of said fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0772] (b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D isa 5-6 membered monocyclic or an 8-10 membered bicyclic aryl orheteroaryl ring;

[0773] (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;and

[0774] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.

[0775] Even more preferred compounds of formula IVc have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0776] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetamido and R^(y) is selected from2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- ordialkylaminoalkoxy, acetamido, optionally substituted phenyl, ormethoxymethyl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, piperidino, or cyclohexoring, wherein said ring is optionally substituted with —halo, —R, —OR,—COR, —CO₂R, —CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂—N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or —SO₂N(R⁴)₂, wherein R is hydrogen or anoptionally substituted C₁₋₆ aliphatic group;

[0777] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring optionally substituted with one ortwo groups selected from —halo, —CN, —No₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂,—N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂;

[0778] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group, and R² ishydrogen; and

[0779] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and

[0780] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring.

[0781] Representative compounds of formula IVc are shown below in Table11. TABLE 11

IVc-1

IVc-2

IVc-3

IVc-4

IVc-5

IVc-6

IVc-7

IVc-8

IVc-9

IVc-10

IVc-11

IVc-12

[0782] In another embodiment, this invention provides a compositioncomprising a compound of formula IVc and a pharmaceutically acceptablecarrier.

[0783] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVc or a pharmaceutical composition thereof.

[0784] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IVc or a compositioncomprising said compound.

[0785] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IVc or apharmaceutical composition thereof.

[0786] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVc or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0787] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IVc or a compositioncomprising said compound.

[0788] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula IVc, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0789] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVc, asdescribed above.

[0790] Another embodiment of this invention relates to compounds offormula IVd:

[0791] or a pharmaceutically acceptable derivative or prodrug thereof,wherein:

[0792] Z¹ is nitrogen or C—R⁸ and Z²is nitrogen or CH, wherein one of Z¹or Z² is nitrogen;

[0793] Q′ is selected from —C(R^(6′))₂—, 1,2-cyclopropanediyl,1,2-cyclobutanediyl, or 1,3 -cyclobutanediyl;

[0794] R^(x) and R^(y) are independently selected from T—R³ or L—Z—R, orR^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³ and eachsubstitutable ring nitrogen of s aid ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

[0795] R¹ is T-(Ring D);

[0796] Ring D is a 5-7 membered monocyclic ring or 8-10 memberedbicyclic ring selected from aryl, heteroaryl, heterocyclyl orcarbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ringheteroatoms selected from nitrogen, oxygen or sulfur, wherein eachsubstitutable ring carbon of Ring D is independently substituted by oxo,T—R⁵, or V—Z—R⁵, and each substitutable ring nitrogen of Ring D isindependently substituted by —R⁴;

[0797] T is a valence bond or a C₁₋₄ alkylidene chain, wherein when Q′is —C(R⁶)₂— a methylene group of said C₁₋₄ alkylidene chain isoptionally replaced by —O—, —S—, —N(R⁴)—, —CO—, —CONH—, —NHCO—, —SO₂—,—SO₂NH—, —NHSO₂—, —CO₂—, —OC(O)—, —OC(O)NH—, or —NHCO₂—;

[0798] Z is a C₁₋₄ alkylidene chain;

[0799] L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)——C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0800] R² and R^(2′) are independently selected from —R, —T—W—R⁶, or R²and R^(2′) are taken together with their intervening atoms to form afused, 5-8 membered, unsaturated or partially unsaturated, ring having0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, whereineach substitutable ring carbon of said fused ring formed by R² andR^(2′) is independently substituted by halo, oxo, —CN, —NO₂, —R⁷, or—V—R⁶, and each substitutable ring nitrogen of said ring formed by R²and R^(2′) is independently substituted by R⁴;

[0801] R³ is selected from —R, —halo, —OR, —C(═O)R, —CO₂R, —COCOR,—COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR, —N(R⁴)₂, —CON(R⁷)₂,—SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂ (C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂, —N(R⁷)SO₂N(R⁷)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂;

[0802] each R is independently selected from hydrogen or an optionallysubstituted group selected from C₁₋₆ aliphatic, C₁₋₆ aryl, a heteroarylring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ringatoms;

[0803] each R⁴ is independently selected from —R⁷, —COR⁷, —CO₂(optionally substituted C₁₋₆ aliphatic), —CON(R⁷)₂, or —SO₂R⁷;

[0804] each R⁵ is independently selected from —R, halo, —OR, —C(═O)R,—CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂,—SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂,—N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂;

[0805] V is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—,—CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R )CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—,—N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—,—C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—;

[0806] W is —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—,—C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —CO—, —CO₂—, —C(R⁶)OC(O)—,—C(R⁶)OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—,—C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—,—C(R⁶)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—;

[0807] each R⁶ is independently selected from hydrogen or an optionallysubstituted C₁₋₄ aliphatic group, or two R⁶ groups on the same nitrogenatom are taken together with the nitrogen atom to form a 5-6 memberedheterocyclyl or heteroaryl ring;

[0808] each R^(6′) is independently selected from hydrogen or a C₁₋₄aliphatic group, or two R^(6′) on the same carbon atom are takentogether to form a 3-6 membered carbocyclic ring;

[0809] each R⁷ is independently selected from hydrogen or an optionallysubstituted C₁₋₆ aliphatic group, or two R⁷ on the same nitrogen aretaken together with the nitrogen to form a 5-8 membered heterocyclyl orheteroaryl ring; and

[0810] R⁸ is selected from —R, halo, —OR, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O) R,—N(R⁴)COR, —N(R⁴)CO₂ (optionally substituted C₁₋₆aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂.

[0811] Preferred rings formed by R^(x) and R^(y) of formula IVd includea 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having0-2 heteroatoms, wherein said R^(x)/R^(y) ring is optionallysubstituted. This provides a bicyclic ring system containing a pyridinering. Preferred pyridine ring systems of formula IVa are shown below.

[0812] More preferred pyridine ring systems of formula IV-d includeIVd-A, IVd-B, IVd-D, IVd-E, IVd-J, IVd-P, and IVd-V, most preferablyIVd-A, IVd-B, IVd-D, IVd-E, and IVd-J. Even more preferred pyridine ringsystems of formula IVd include those described above, wherein Z¹ isnitrogen and Z² is CH.

[0813] Preferred R^(x) groups of formula IVd include hydrogen, alkyl- ordialkylamino, acetamido, or a C₁₋₄ aliphatic group such as methyl,ethyl, cyclopropyl, or isopropyl.

[0814] Preferred R^(y) groups of formula IVd include T—R³ or L—Z—R³wherein T is a valence bond or a methylene, L is —O—, —S—, or —N(R⁴)—,—C(R⁶)₂O—, —CO— and R³ is —R, —N(R⁴)₂, or —OR. Examples of preferredR^(y) groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl,t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such asmethoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylaminoor dimethylamino, alkyl- or dialkylaminoalkoxy such asdimethylaminopropyloxy, acetamido, optionally substituted phenyl such asphenyl or halo-substituted phenyl.

[0815] The ring formed when the R^(x) and R^(y) groups of formula IVdare taken together may be substituted or unsubstituted. Suitablesubstituents include —R, halo, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —OR,—N(R⁴)—(CH₂)₂₋₄—N(R⁴)₂, —N(R⁴)—(CH₂)₂₋₄—R, —C(═O)R, —CO₂R, —COCOR, —NO₂,—CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂, —CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R,—N(R⁴)COR, —N(R⁴)CO₂(optionally substituted C₁₋₆ aliphatic),—N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁴)CON(R⁴Y₂, —N(R⁴)SO₂N(R⁴)₂,—N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂, R and R⁴ are as defined above. PreferredR^(x)/R^(y) ring substituents include —halo, —R, —OR, —COR, —CO₂R,—CON(R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, , —NO₂ —N(R⁴)₂,—NR⁴COR, —NR⁴SO₂R, —SO₂N(R⁴)₂ wherein R is hydrogen or an optionallysubstituted C₁₋₆ aliphatic group.

[0816] The R² and R^(2′) groups of formula IVd may be taken together toform a fused ring, thus providing a bicyclic ring system containing apyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido,and a partially unsaturated 6-membered carbocyclo ring. These areexemplified in the following formula IVd compounds having apyrazole-containing bicyclic ring system:

[0817] Preferred substituents on the R²/R^(2′) fused ring of formula IVdinclude one or more of the following: —halo, —N(R⁴)₂, —C₁₋₄ alkyl, —C₁₋₄haloalkyl, —NO₂, —O(C₁₋₄ alkyl), —CO₂(C₁₋₄alkyl), —CN, —SO₂(C₁₋₄alkyl),—SO₂NH₂, —OC(O)NH₂, —NH₂SO₂(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —C(O)NH₂,and —CO(C₁₋₄ alkyl), wherein the (C₁₋₄ alkyl) is a straight, branched,or cyclic alkyl group. Preferably, the (C₁₋₄ alkyl) group is methyl.

[0818] When the pyrazole ring system of formula IVd is monocyclic,preferred R² groups include hydrogen or a substituted or unsubstitutedgroup selected from aryl, heteroaryl, or a C₁₋₆ aliphatic group.Examples of such preferred R² groups include H, methyl, ethyl, propyl,cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, andbenzyloxypropyl. A preferred R^(2′) group is hydrogen.

[0819] When Ring D of formula IVd is monocyclic, preferred Ring D groupsinclude phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0820] When Ring D of formula IVd is bicyclic, preferred bicyclic Ring Dgroups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl,quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl,benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

[0821] On Ring D of formula IVd, preferred T—R⁵ or V—Z—R⁵ substituentsinclude —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴) SO₂R, —N(R⁶) COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, and—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring. More preferred R⁵ substituents include —Cl, —Br, —F,—CN, —CF₃, —COOH, —CONHMe, —CONHEt, —NH₂, —NHAc, —NHSO₂Me, —NHSO₂Et,—NHSO₂ (n-propyl), —NHSO₂(isopropyl), —NHCOEt, —NHCOCH₂NHCH₃,—NHCOCH₂N(CO₂t—Bu)CH₃, —NHCOCH₂N(CH₃)₂, —NHCOCH₂CH₂N(CH₃)₂,—NHCOCH₂CH₂CH₂N(CH₃)₂, —NHCO(cyclopropyl), —NHCO(isobutyl),—NHCOCH₂(morpholin-4-yl), —NHCOCH₂CH₂ (morpholin-4-yl), —NHCOCH₂CH₂CH₂(morpholin-4-yl), —NHCO₂(t-butyl), —NH(C₁₋₄ aliphatic) such as —NHMe,—N(C₁₋₄ aliphatic)₂ such as —NMe₂, OH, —O(C₁₋₄ aliphatic) such as —OMe,C₁₋₄ aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, ort-butyl, and —CO₂(C₁₋₄ aliphatic).

[0822] Preferred R⁸ groups of formula IVd, when present, include R, OR,and N(R⁴)₂. Examples of preferred R⁸ include methyl, ethyl, NH₂,NH₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂NH, N(CH₃)₂CH₂CH₂O, (piperidin-1-yl)CH₂CH₂O,and NH₂CH₂CH₂O—

[0823] Preferred Q′ groups of formula IVd include —C(R^(6′))₂— or1,2-cyclopropanediyl, wherein each R^(6′) is independently selected fromhydrogen or methyl. A more preferred Q′ group is —CH₂—.

[0824] Preferred formula IVd compounds have one or more, and morepreferably all, of the features selected from the group consisting of:

[0825] (a) R^(x) is hydrogen, alkyl- or dialkylamino, acetamido, or aC₁₋₄ aliphatic group and R^(y) is T—R³ or L—Z—R³, wherein T is a valencebond or a methylene and R³ is —R, —N(R⁴)₂, or —OR; or R^(x) and R^(y)are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-2heteroatoms selected from oxygen, sulfur, or nitrogen, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴;

[0826] (b) R¹ is T-(Ring D), wherein T is a valence bond or a methyleneunit and wherein said methylene unit is optionally replaced by —O—,—NH—, or —S—;

[0827] (c) Ring D is a 5-7 membered monocyclic or an 8-10 memberedbicyclic aryl or heteroaryl ring; and

[0828] (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen, or R² and R^(2′)are taken together to form an optionally substituted benzo ring.

[0829] More preferred compounds of formula IVd have one or more, andmore preferably all, of the features selected from the group consistingof:

[0830] (a) R^(y) is T—R³ or L—Z—R³ wherein T is a valence bond or amethylene and R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl; or R^(x) and R^(y) are takentogether with their intervening atoms to form a benzo, pyrido,cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring,wherein each substitutable ring carbon of said, fused ring formed byR^(x) and R^(y) is independently substituted by oxo, T—R³, or L—Z—R³,and each substitutable ring nitrogen of said ring formed by R^(x) andR^(y) is independently substituted by R⁴;

[0831] (b) R¹ is T-(Ring D), wherein T is a valence bond, and Ring D isa 5-6 membered monocyclic or an 8-10 membered bicyclic aryl orheteroaryl ring;

[0832] (c) R2 is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring;

[0833] (d) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, or 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —N(R⁴ )—; and

[0834] (e) Q′ is —C(R^(6′))₂— or 1,2-cyclopropanediyl, wherein eachR^(6′) is independently selected from hydrogen or methyl.

[0835] Even more preferred compounds of formula IVd have one or more,and more preferably all, of the features selected from the groupconsisting of:

[0836] (a) R^(x) is hydrogen methyl, ethyl, propyl, cyclopropyl,isopropyl, methylamino or acetamido and R^(y) is selected from2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl,alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- ordialkylaminoalkoxy, acetamido, optionally substituted phenyl, ormethoxymethyl; or R^(x) and R^(y) are taken together with theirintervening atoms to form a benzo, pyrido, piperidino, or cyclohexoring, wherein said ring is optionally substituted with —halo, —R, —OR,—COR, —CO₂R, —CON (R⁴)₂, —CN, —O(CH₂)₂₋₄—N(R⁴)₂, —O(CH₂)₂₋₄—R, —NO₂—N(R⁴)₂, —NR⁴COR, —NR⁴SO₂R, or —SO₂N(R⁴)₂, wherein R is hydrogen or anoptionally substituted C₁₋₆ aliphatic group;

[0837] (b) R¹ is T-(Ring D), wherein T is a valence bond and Ring D is a5-6 membered aryl or heteroaryl ring optionally substituted with one ortwo groups selected from —halo, —CN, —NO₂, —N(R⁴)₂, optionallysubstituted C₁₋₆ aliphatic, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR,—N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂,—N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶ )COCH₂CH₂CH₂N(R⁴)₂;

[0838] (c) R² is hydrogen or a substituted or unsubstituted groupselected from aryl, heteroaryl, or a C₁₋₆ aliphatic group, and R^(2′) ishydrogen; and

[0839] (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—;

[0840] (e) Ring D is substituted by up to three substituents selectedfrom —halo, —CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphaticgroup, —OR, —C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂,—N(R⁴)SO₂R, —N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or—N(R⁶)COCH₂CH₂CH₂N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring; and

[0841] (f) Q′ is —CH₂—.

[0842] Representative compounds of formula IVd are shown below in Table12. TABLE 12

IVd-1

IVd-2

IVd-3

IVd-4

IVd-5

IVd-6

IVd-7

IVd-8

[0843] In another embodiment, this invention provides a compositioncomprising a compound of formula IVd and a pharmaceutically acceptablecarrier.

[0844] Another aspect of this invention relates to a method of treatingor preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor,which method comprises administering to a patient in need of such atreatment a therapeutically effective amount of a compound of formulaIVd or a pharmaceutical composition thereof.

[0845] Another aspect of this invention relates to a method ofinhibiting Aurora-2 activity in a patient, which method comprisesadministering to the patient a compound of formula IVd or a compositioncomprising said compound.

[0846] Another aspect of this invention relates to a method of treatingor preventing a GSK-3-mediated disease with a GSK-3 inhibitor, whichmethod comprises administering to a patient in need of such a treatmenta therapeutically effective amount of a compound of formula IVd or apharmaceutical composition thereof.

[0847] One aspect of this invention relates to a method of enhancingglycogen synthesis and/or lowering blood levels of glucose in a patientin need thereof, which method comprises administering to the patient atherapeutically effective amount of a compound of formula IVd or apharmaceutical composition thereof. This method is especially useful fordiabetic patients. Another method relates to inhibiting the productionof hyperphosphorylated Tau protein, which is useful in halting orslowing the progression of Alzheimer's disease. Another method relatesto inhibiting the phosphorylation of β-catenin, which is useful fortreating schizophrenia.

[0848] Another aspect of this invention relates to a method ofinhibiting GSK-3 activity in a patient, which method comprisesadministering to the patient a compound of formula IVd or a compositioncomprising said compound.

[0849] Another method relates to inhibiting Aurora-2 or GSK-3 activityin a biological sample, which method comprises contacting the biologicalsample with the Aurora-2 or GSK-3 inhibitor of formula Ivd, or apharmaceutical composition thereof, in an amount effective to inhibitAurora-2 or GSK-3.

[0850] Each of the aforementioned methods directed to the inhibition ofAurora-2 or GSK-3, or the treatment of a disease alleviated thereby, ispreferably carried out with a preferred compound of formula IVd, asdescribed above.

[0851] The compounds of this invention may be prepared in general bymethods known to those skilled in the art for analogous compounds, asillustrated by the general Schemes I-VII, the general-methods thatfollow, and by the preparative examples below.

[0852] Reagents: (a) EtOH, Et₃N, room temperature; (b) R¹—QH (Q═S, NH orO) or R¹—CH₂—M/catalyst (M is Al or Mg or Sn, catalyst═Pd° or Ni°)

[0853] Scheme I above shows a general route for the preparation of thepresent compounds. The dichlorinated starting material 1 may be preparedusing methods similar to the those reported in J. Indian. Chem. Soc.,61, 690-693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994). Thereaction of 1 with aminopyrazole (or aminoindazole) 2 in a manner asdescribed in Bioorg. Med. Chem. Lett, 10, 11, 1175-1180, (2000) or in J.Het. Chem, 21, 1161-1167, (1984) provides the versatile monochlorointermediate 3. Conditions for displacing the chloro group of 3 by R¹—Qwill depend on the nature of the Q linker moiety and are generally knownin the field. See, for example, J. Med. Chem, 38, 14, 2763-2773, (1995)(where Q is an N-Link), or Chem. Pharm. Bull., 40, 1, 227-229, (1992)(S—Link), or J. Het. Chem., 21, 1161-1167, (1984) (O-Link) or Bioorg.Med. Chem. Lett, 8, 20, 2891-2896, (1998) (C-Link).

[0854] Reagents: (a) POCl₃, Pr₃N, 110° C.; (b) EtOH, Et₃N, roomtemperature.

[0855] Scheme II above shows an alternative route for the preparation ofthe present compounds. The starting material 4 may be prepared in amanner similar to that described for analogous compounds. See Chem.Heterocycl. Compd., 35, 7, 818-820 (1999) (where Q is an N-Link), IndianJ. Chem. Sect. B. 22, 1, 37-42 (1983) (N-Link), Pestic. Sci, 47, 2,103-114 (1996) (O-Link), J. Med. Chem., 23, 8, 913-918 (1980) (S-Link),or Pharmazie, 43, 7, 475-476 (1988) (C-Link). The chlorination of 4provides intermediate 5. See J. Med. Chem., 43, 22, 4288-4312 (2000) (Qis an N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (O-Link), J. Med.Chem., 41, 20, 3793-3803 (1998) (S—Link), or J. Med. Chem., 43, 22,4288-4312 (2000) (C—Link). Displacement of the 4-Cl group inintermediate 5 with aminopyrazole (or aminoindazole) 2 to providecompounds of this invention may be performed according to known methodsfor analogous compounds. See J. Med. Chem., 38, 14, 2763-2773 (1995)(where Q is an N-Link), Bioorg. Med. Chem. Lett ., 7 , 4, 421-424 (1997)(O-Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-Link), orJ. Med. Chem., 41, 21, 4021-4035 (1998) (C-Link).

[0856] Reagents: (a) POCl₃; (b) EtOH, Et₃N, room temperature; (c) Oxone;(d) R¹—QH (Q═S, NH or O) or R¹—CH₂—M/catalyst (M is Al or Mg or Sn,catalyst═Pd° or Ni°)

[0857] Scheme III above shows another alternative route for preparingthe present compounds. The starting material 6 may be chlorinated toprovide intermediate 7. Displacement of the 4-chloro group in 7 withaminopyrazole (or aminoindazole) 2 gives intermediate 8 which, uponoxidation of the methylsulfanyl group, provides the methylsulfone 9. Themethylsulfonyl group of 9 may be displaced readily with R¹—QH to givethe desired product I. See J. Am. Chem. Soc., 81, 5997-6006 (1959)(where Q is an N-Link)or in Bioorg. Med. Chem. Lett., 10, 8, 821-826(2000) (S-Link).

[0858] Reagents: (a) POCl₃; (b) EtOH, Et₃N, room temperature; (c)R^(y)—H (R═S, NH or O); (d) oxone; (e) R¹—QH (Q═S, NH or O) orR—CH₂—M/catalyst (M is Al or Mg or Sn catalyst═Pd° or Ni°)

[0859] Scheme IV above shows a general route for the preparation of thepresent compounds wherein R^(y) is a group attached to the pyrimidinecore via a nitrogen, oxygen or sulfur heteroatom. The starting 4,6-dihydroxy-2-methylsulfanylpyrimidine 10 may be prepared as describedin J. Med. Chem., 27, 12, 1621-1629 (1984). The chloro groups ofintermediate 11 may be displaced sequentially with aminopyrazole (oraminoindazole) 2 and then with another amine (or alcohol or thiol)following procedures similar to those reported in U.S. Pat. No.2,585,906 (ICI, 1949). The methylsulfanyl group of 13 may then beoxidized to provide the methylsulfone 14. Displacement of themethylsulfonyl group of 14 gives the desired product II.

[0860] Scheme V above shows general routes for the preparation ofcompounds of formulae IVa, IVb, IVc, and Ivd. Steps (a) and (b) areanalogous to the corresponding steps described in Scheme I above. SeeIndian J. Chem. Sect. B, 34, 9, 1995, 778-790; J. Chem. Soc., 1947,899-905; J. Chem. Soc., 34, 9, 1948, 777-782; and Indian J. Chem., 1967,467-470.

[0861] The synthetic transformations shown in Schemes I-IV above arefurther illustrated by the following methods.

[0862] Scheme VI above shows a general route for preparing the arylguanidine intermediate used to prepare compounds where Q is—C(R^(6′))₂—. The mono- or bis-alkylation of 19 at step (a) to preparecompound 20 can be achieved by using methods substantially similar tothose described by Jeffery, J. E., et al, J. Chem Soc, Perkin Trans 1,1996 (21) 2583-2589; Gnecco, D., et al, Org Prep Proced Int, 1996, 28(4), 478-480; Fedorynski, M. and Jonczyk, A., Org Prep Proced Int, 1995,27 (3), 355-359; Suzuki, S, et al, Can J Chem, 1994, 71 (2) 357-361; andPrasad, G., et al, J Org Chem, 1991, (25), 7188-7190. The method of step(b) to prepare compound 21 from compound 20 can be achieved by usingmethods substantially similar to those described by Moss, R., et is al,Tetrahedron Lett, 1995, (48), 8761-8764 and Garigipati, R., TetrahedronLett, 1990, (14), 1969-1972.

[0863] The aryl guanidine intermediates prepared according to Scheme VImay then be used to prepare the compounds of this invention by themethods described in the above Schemes I—V and by methods known to oneskilled in the art.

[0864] Scheme VII above shows a general method that may be used toprepare compounds of formula II wherein Q is 1,2-cyclopropanediyl.Compound 26 may then be used to prepare the desired amino-pyrazolecompounds using the methods described above at Scheme I step (b).

[0865] Method A. To a solution of 2,4-dichloroquinazoline (12.69 g, 63mmol) and 3-amino-5-methylpyrazole (6.18 g, 63 mmol) in ethanol (220 mL)is added triethylamine (8.13 mL, 63 mmol) and the reaction mixture isstirred for 3 hours at room temperature. The pale yellow precipitate isthen collected by filtration, washed with cold ethanol and dried undervacuum to give(2-chloroquinazolin-4-yl)—(5-methyl-2H-pyrazol-3-yl)-amine.

[0866] The above-prepared(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (155 mg, 0.6mmol) and 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed intert-butanol (3 mL) over 20 h. The mixture is concentrated in vacuo andthe residue is suspended in EtOH/H₂O (1 mL/3 mL). K₂CO₃ (83 mg, 0.6mmol) is added and the suspension is stirred for 2h at room temperature.The solid that forms is collected and dried under vacuum to give theproduct[2-(3-chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0867] Method B. Sodium hydride (45 mg, 1.12 mmol) in THF (2 mL) istreated with 3-methoxyphenol (0.94 g, 7.6 mmol) and the reaction mixtureis stirred until effervescence ceases. The THF is removed in vacuo andthe above-prepared(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (150 mg, 0.51mmol)) is added. The reaction mixture is stirred at 100° C. for 20 h,then poured into aqueous K₂CO₃ and stirred for 2h at room temperature.The solid that forms is collected and re-crystallized from ethanol togive the product[2-(3-methoxyphenoxy)-qainazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0868] Method C. To a solution of 4-hydroxy-2-phenoxymethylquinazoline(2 g, 7.93 mmol) in phosphorus oxychloride (10 mL) is addedtripropylamine (3.02 mL, 15.8 mmol) and the reaction mixture is heatedfor 30 minutes at 110° C. The excess phosphorus oxychloride isevaporated in vacuo, the residue is poured on ice cold aqueous NaHCO₃and extracted with ethyl acetate. The organic layer is washed withbrine, dried, filtered and evaporated. The resulting residue is purifiedon flash chromatography (SiO₂, hexane /AcOEt gradient) to give4-chloro-2-phenoxymethylquinazoline.

[0869] To a solution of the above 4-chloro-2-phenoxymethylquinazoline(0.5 g, 1.85 mmol) in THF (30 mL) is added 3-amino-5-cyclopropylpyrazole(0.47 g, 3.69 mmol) and the reaction mixture is heated at 65° C. for 24hours. Solvent is evaporated and ethanol is added. A white solid formsand is collected by filtration and dried under vacuum to give(5-cCyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.

[0870] Method D. To a solution of the above-prepared(2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg,0.43 mmol) in THF (5 mL) is added NiCl₂(dppp) (12 mg, 2.1.10⁻⁵ mol),followed by 1M benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol). Thesolution is heated at 50° C. for 20 hours and the reaction mixture isthen quenched with aqueous NH₄Cl and the product extracted in ethylacetate. The solvent is evaporated and the residue purified by flashchromatography to yield the desired(2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

[0871] Method E. A solution of(2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed intert-butanol (3 mL) over a 20 hour period. Diethylether (10 mL) is addedto the mixture and a solid forms that is collected by filtration. Thissolid is suspended in EtOH/H₂O 1 mL/3 mL), then K₂CO₃ (110 mg, 0.8 mmol)is added and the suspension is stirred for 2 h at room temperature. Asolid forms and is collected and dried under vacuum to give the product[2-(4-acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0872] Method F. To a solution of2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10 mL) isadded triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368mg, 2.46 mmol) and the reaction mixture is heated at 90° C. for 20 h.The reaction mixture is partitioned between ethyl acetate and aqueoussaturated NaHCO₃. The organic layer is washed with brine and evaporatedin vacuo. The residue is purified by flash chromatography (SiO₂,hexane/AcOEt gradient) to give(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

[0873] The above-prepared(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amineis reacted with 2-naphthalene mercaptan as described in Method L toyield the desired(5-cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)—5,6,7,8-tetrahydroquinazolin-4-yl]-amine.

[0874] Method G. A solution of(5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine(110 mg, 0.26 mmol) in a mixture of THF/water (1/1, 10 mL) is treatedwith 1M LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hoursat room temperature and then neutralized with 1M HCl (0.75 mL, 0.75mmol). A solid forms and is collected by filtration to afford thedesired[2-(3-carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

[0875] Method H. A solution of[2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(23 mg, 5.54.10⁻⁵ mol) in dichloroethane (3 mL) is treated with 1M BBr₃in dichloromethane (222 μL, 2.21.10⁻⁴ mol). The mixture os heated at 80°C. for 4 hours before 1M BBr₃ in DCM (222 μL, 2.21.10⁻⁴ mol) is added.The reaction mixture is heated at 80° C. for a further 3 hours. Thesolvent is evaporated and methanol is added to the residue to quenchresidual BBr₃. The solvent is evaporated in vacuo and this operationrepeated 3 times. 1M HCl (2 mL) is added to the solid residue and thesuspension stirred at room temperature for 15 hours. The solid iscollected by filtration and suspended in a mixture water/EtOH (3/1, 8mL). The mixture is neutralized with NaHCO₃ and stirred for 2 hours atroom temperature. The solid is then collected by filtration, rinsed withwater and diethyl ether to give the desired[2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0876] Method I. To a solution of[2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(32 mg, 7.87.10⁻⁵ mol) in DMF (1 mL) is added potassium carbonate (65mg, 4.72.10⁻⁴ mol) and the reaction mixture is heated to 80° C.N—(3-chloropropyl)morpholine (39 mg, 2.36.10⁻⁴ mol) is then added, andthe mixture is stirred at 80° C. for 4 hours, cooled to room temperatureand the solvent is evaporated. The resulting residue is purified byflash chromatography to afford the desired[2-(4-acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0877] Method J. To a solution of[2-(4-acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(147 mg, 3.38.10⁻⁴ mol) in methanol (5 mL) is added Pd/C 10% (40 mg) andthe reaction mixture is treated with hydrogen at balloon pressure at 45°C. for 20 hours. The catalyst is filtered through a pad of celite whichis then washed with dilute HCl. The combined yellow filtrate isevaporated and the resulting solid residue is crystallized from methanolto afford the desired[2-(4-acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0878] Method K.[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(182 mg, 4.18.10⁻⁴ mol) is dissolved in a mixture EtOH/water/AcOH(25/10/1, 36 mL) and the reaction is heated at 90° C. Iron powder (93mg) is added and the mixture is stirred at 90° C. for 4 hours, cooled toroom temperature and filtered through a pad of celite. The pad is washedwith methanol and the combined filtrate is concentrated in vacuo. Theresidue is purified by flash chromatography (SiO₂, DCM/MeOH gradient) togive the desired[2-(4-acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0879] Method L. To a solution of 2,4-dichloro-6-phenyl-pyrimidine (300mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF(7 mL) is added triethylamine (195 μL, 1.40 mmol) followed by sodiumiodide (200 mg, 1.33 mmol) and the reaction mixture is stirred for 15hours at 90° C. The resulting solution is partitioned between ethylacetate and water and the organic phase washed with brine, dried overMgSO₄ then concentrated in vacuo. The residue is triturated in methanoland the resulting white solid collected by filtration to afford(2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (236mg, 62%).

[0880] The above prepared(2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60mg, 0.21 mmol) is combined with 4-acetamidothiophenol (176 mg, 1.05mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20hours. The reaction mixture is cooled to room temperature andpartitioned between ethyl acetate and aqueous NaHCO₃. The organic layeris washed with brine, dried over MgSO₄ and concentrated in vacuo. Theresulting residue is purified by flash chromatography (SiO₂, DCM/MeOHgradient) to afford[2-(4-acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(74 mg, 85%)

[0881] Method M. To a suspension of 4,6-dihydroxymercaptopyrimidine (8g, 55 mmol) in a mixture of EtOH/water (1/1, 140 mL) is added NaOH (2.33g, 58.3 mmol) followed by 4-methoxybenzyl chloride (7.90 mL, 58.3 mmol).The solution is stirred for 1.5 hours at 60° C. and then at roomtemperature for a further 6 hours. The resulting white precipitate iscollected by filtration to give4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine.

[0882] The above-prepared4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine (2.5 g, 9.46 mmol)is suspended in POCl₃ (20 mL), and tripropylamine (3.60 mL, 18.9 mmol)is added dropwise to the mixture. The reaction is then heated at 110° C.for 4 hours. The brown solution is cooled to room temperature and thesolvent is evaporated. The residue is poured on ice cold NaHCO₃ and theproduct is then extracted with ethyl acetate. The organic phase is driedover MgSO₄, concentrated in vacuo and the residue is purified by flashchromatography (SiO₂, hexane/AcOEt gradient) to give4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine.

[0883] To a solution of above-prepared4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol)and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH (20 mL) isadded diisopropylethylamine (0.56 mL, 3.19 mmol) followed by sodiumiodide (455 mg, 3.04 mmol). The reaction mixture is stirred for 15 hoursat 120° C. The solvent is removed in vacuo and the residue is purifiedby flash chromatography (SiO₂, hexane/AcOEt gardient) to give[6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.

[0884] The above-prepared[6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(S-methyl-2H-pyrazol-3-yl)-amine(500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130° C.for 15 hours. The solvent is then removed in vacuo and the residue ispurified by flash chromatography (SiO₂, dichloromethane/MeOH gradient)to give the desired product(2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0885] Method N. A solution of[2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(100 mg, 2.24.10⁻⁴ mol) in dichloroethane (5 mL) is treated with 1M BBr₃in DCM (896 μL, 8.96.10⁻⁴ mol). The mixture is then heated at 80° C. for4 hours before 1M BBr₃ in DCM (896 μL, 8.96.10⁻⁴ mol) is added. Thereaction mixture is then heated at 80° C. for a further 3 hours. Thesolvent is evaporated and methanol is added to the residue to quench anyresidual BBr₃. The solvent is evaporated in vacuo and this evaporationstep is repeated 3 times. 1M HCl(8 mL) is added to the solid residue andthe suspension is stirred at room temperature for 15 hours. The solid iscollected by filtration and suspended in a mixture of water/EtOH (3/1,24 mL). The mixture is neutralized with NaHCO₃ and stirred for 2 hoursat room temperature. The solid is then collected by filtration, rinsedwith water and with diethyl ether to give[2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0886] To a solution of the above-prepared[2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(70 mg, 1.62.10⁻⁴ mol) in DMF (3 mL) is added potassium carbonate (134mg, 9.71.10⁻⁴ mol). The reaction mixture is heated to 80° C. before1-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10⁻⁴ mol) isadded. The mixture is stirred at 80° C. for 4 hours, cooled to roomtemperature and the solvent is evaporated. The residue is purified byflash chromatography to afford the desired product{2-(4-acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine.

[0887] Method O. To a solution of[6-methoxycarbonyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(2 g, 4.85 mmol) in THF (100 mL) is added lithium borohydride (0.32 g,14.5 mmol). The reaction mixture is stirred at 50° C. for 1.5 hours. Thereaction is then quenched with dilute HCl and extracted with ethylacetate. The organic layer is successively washed with aqueous saturatedNaHCO₃ and brine, dried over MgSO₄ and evaporated. The solid residue istriturated in ethyl acetate and the resulting white solid is collectedby filtration to give the desired product[6-hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0888] Method P. To a solution of4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is addeddiisopropylethylamine (4.69 mL, 26.9 mmol) followed by sodium iodide(3.84 g, 25.6 mmol). The reaction mixture is stirred for 15 hours at120° C. The solvent is then removed in vacuo and the residue is purifiedby flash chromatography (SiO₂, hexane/AcOEt gradient) to give[6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.

[0889] The above-prepared[6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(2.42 g, 9.46 mmol) is heated in morpholine (10 mL) at 130° C. for 15hours. The solvent is then removed in vacuo and the solid residue istriturated in EtOH and collected by filtration to give[2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0890] To a suspension of the above-prepared[2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(500 mg, 1.63 mmol) in MeOH (10 mL) is added a solution of oxone (3.0 g)in water (10 mL). The reaction mixture is stirred at room temperaturefor 15 hours and most of the solvent is evaporated. The residue ispartitioned between DCM and aqueous saturated NaHCO₃. The organic layeris washed with brine, dried, filtered and evaporated. The residue istriturated in MeOH and the resulting white solid is collected byfiltration to give[2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine.

[0891] The above-prepared[2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(178 mg, 0.52 mmol) and 4-acetamidothiophenol (176 mg, 1.05 mmol) arerefluxed in tert-butanol (5 mL) over 20 h. The reaction mixture iscooled to room temperature and partitioned between ethyl acetate andaqueous NaHCO₃. The organic layer is washed with brine, dried over MgSO₄and concentrated in vacuo. The residue is purified by flashchromatography to give the desired product[2-(4-acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

[0892] In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES

[0893] The following HPLC methods were used in the analysis of thecompounds as specified in the Synthetic Examples set forth below. Asused herein, the term “R_(t)” refers to the retention time observed forthe compound using the HPLC method specified.

[0894] HPLC—Method A:

[0895] Column: C18, 3 um, 2.1×50 mm, “Lighting” by Jones Chromatography.

[0896] Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100%acetonitrile for 1.4 min and return to initial conditions. Total runtime 7.0 min. Flow rate: 0.8 mL/min.

[0897] HPLC—Method B:

[0898] Column: C18, 5 um, 4.6×150 mm “Dynamax” by Rainin Gradient: 100%water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile(containing 0.1% TFA) over 20 min, hold at 100% acetonitrile for 7.0 minand return to initial conditions. Total run time 31.5 min. Flow rate:1.0 mL/min.

[0899] HPLC—Method C:

[0900] Column: Cyano, 5 um, 4.6×150 mm “Microsorb” by Varian.

[0901] Gradient: 99% water (0.1% TFA), 1% acetonitrile (containing 0.1%TFA) to 50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA)over 20 min, hold for 8.0 min and return to initial conditions. Totalrun time 30 min. Flow rate: 1.0 mL/min.

[0902] HPLC—Method D:

[0903] Column: Waters (YMC) ODS-AQ 2.0×50 mm, S5, 120A.

[0904] Gradient: 90% water (0.2% Formic acid), 10% acetonitrile(containing 0.1% Formic acid) to 10% water (0.1% formic acid), 90%acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for 0.8min and return to initial conditions. Total run time 7.0 min.

[0905] Flow rate: 1.0 mL/min.

[0906] HPLC—Method E:

[0907] Column: 50×2.0 mm Hypersil C18 BDS;5 μm

[0908] Gradient: elution 100% water (0.1% TFA), to 5% water (0.1% TFA),95% acetonitrile (containing 0.1% TFA) over 2.1 min, returning toinitial conditions after 2.3 min.

[0909] Flow rate: 1 mL/min.

Example 1

[0910](5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine(IIa-1):

[0911] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp >300° C. (dec.); ¹H NMR (DMSO) δ2.07(3H,s), 5.54(1H, s), 7.38(1H, m), 7.56-7.45(4H, m), 7.65(2H, m), 7.73 (1H,m), 8.55(1H, d), 10.43(1H, s), 12.05(1H, br s); IR (solid) 3259, 3170,3109, 1618, 1594, 1565, 1525, 1476; MS 334.0 (M+H)⁺

Example 2

[0912][2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-2):

[0913] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 259-260° C.; ¹H NMR (DMSO) δ2.12 (3H, s),5.40 (1H, s), 7.60 (1H, t), 7.64 (2H, d), 7.76 (3H, d), 7.92 (1H, t),8.70 (1H, d) 11.50 (1H, br s); IR (solid) 1627, 1606, 1557, 1484, 1473,1433, 1400, 1339, 1286, 1219; MS 368.0 (M+H)⁺

Example 3

[0914][2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-3):

[0915] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 258-259° C.; ¹H NMR (DMSO) δ 2.12 (3H,s), 5.40 (1H, s), 7.54 (1H, t), 7.63 (1H, m), 7.68 (1H, d), 7.86 (1H,t), 7.92 (1H, d), 7.96 (1H, d), 8.66 (1H, d) 11.20 (1H, br s); IR(solid) 1623, 1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0(M+H)⁺

Example 4

[0916][2-(4-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-4):

[0917] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 264-268° C.; ¹H NMR (DMSO) δ 2.04 (3H,s), 3.85 (3H, s), 5.43 (1H, s), 7.12 (2H, d), 7.53 (1H, t), 7.61 (3H,d), 7.84 (3H, t), 8.63 (1H, d), 11.09 (1H, br s), 12.30 (1H, br s); IR(solid) 1622, 1598, 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171,1161; MS 364.1 (M+H)⁺

Example 5

[0918][2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-5):

[0919] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 205-208° C.; ¹H NMR (DMSO) δ 2.05 (3H,s), 5.19 (1H, s), 7.38 (1H, t), 7.52-7.64 (3H, m), 7.68 (2H, d), 7.90(1H, t), 8.68 (1H, d); IR (solid) 3262, 2967, 1632, 1605, 1558, 1492,1434, 1403, 1344, 1294, 1224, 1162; MS 362.1 (M+H)⁺

Example 6

[0920]{2-[2,4—Bis(trifluoromethyl)phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-6):

[0921] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp >300° C.; ¹H NMR (DMSO) δ 1.98 (3H, S),5.37 (1H, S), 7.50 (1H, t), 7.59 (2H, d), 7.84 (1H, d), 8.32 (1H, s),8.40 (2H, s), 8.66 (1H, d), 10.73 (1H, br s); IR (solid) 1628, 1603,1577, 1548, 1512, 1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470.1(M+H)⁺

Example 7

[0922][2-(2-Chlorophenylsulfanyl)—quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-7):

[0923] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 262-263° C.; ¹H NMR (DMSO) δ 2.05 (3H,s), 5.35 (1H, s), 7.52 (2H, t), 7.65 (2H, m), 7.74 (1H, d), 7.83 (1H,t), 7.88 (1H, d), 8.62 (1H, d), 10.97 (1H, br s); IR (solid) 1621, 1603,1569, 1544, 1491, 1448, 1400, 1376, 1336, 1288, 1208; MS 368.0 (M+H)⁺

Example 8

[0924][2-(2,3-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-8):

[0925] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp >300° C.; ¹H NMR (DMSO) δ 2.05 (3H, s),5.34 (1H, s), 7.50 (2H, m), 7.60 (1H, d), 7.75 (1H, t), 7.88 (2H, m),8.62 (1H, d), 10.72 (1H, br s); IR (solid) 1632, 1609, 1561, 1532, 1492,1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M+H)⁺

Example 9

[0926][2-(3-Chlorophenylsulfanyl)—quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-9):

[0927] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 248-249° C.; ¹H NMR (DMSO) δ 2.05 (3H,s), 5.42 (1H, s), 7.55 (2H, m), 7.66 (3H, m), 7.81 (1H, s), 7.85 (1H,t), 8.62 (1H, d), 11.10 (1H, br s); IR (solid) 1628, 1611, 1551, 1487,1432, 1410, 1341, 1292, 1217, 1165; MS 368.0 (M+H)⁺

Example 10

[0928][2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-10):

[0929] Prepared in a manner similar to the above described Method E toafford an off white solid, mp 255-256° C.; ¹H NMR (DMSO) δ 2.19 (3H, s),3.59 (1H, s), 5.51 (1H, s), 7.18 (1H, s), 7.45 (1H, t), 7.57 (1H, s),7.59 (1H, d), 7.77 (1H, t), 8.57 (1H, d), 10.57 (1H, s), 12.13 (1H, brs); IR (solid) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292,1278, 1211; MS 338.2 (M+H)⁺

Example 11

[0930][2-(2-Hydroxyphenylsulfanyl)—quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-11):

[0931] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 273-275° C.; ¹H NMR (DMSO) δ 2.06 (3H,s), 5.41 (1H, s), 6.99 (1H, t), 7.07 (1H, d), 7.50 (1H, t), 7.57-7.62(2H, m), 7.73 (1H, d), 7.94 (1H, t), 8.71 (1H, d), 10.29 (1H, br s),11.66 (1H, br s); IR (solid) 1623, 1597, 1552, 1485, 1442, 1404, 1354,1341, 1289, 1221, 1165; MS 350.1 (M+H)⁺

Example 12

[0932][2-(2,4-Difluorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-12):

[0933] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 256-258° C.; ¹H NMR (DMSO) 2.10 (3H, s),5.41 (1H, s), 7.33 (1H, t), 7.51-7.58 (2H, m), 7.65 (1H, d), 7.82-7.91(2H, m), 8.63 (1H, d), 11.06 (1H, br s); IR (solid) 1626, 1608, 1556,1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 (M+H)⁺

Example 13

[0934][2-(3,4-Dimethoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-13):

[0935] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 229-232° C.; 1H NMR (DMSO) δ 2.05 (3H,s), 3.70 (3H, s), 3.85 (3H, s), 5.39 (1H, s), 6.95 (1H, d), 7.30 (2H,d), 7.60 (1H, t), 7.77 (1H, d), 7.94 (1H, t), 8.72 (1H, d), 11.66 (1H,br s); IR (solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254,1237, 1218, 1161, 1137, MS 394.1 (M+H)⁺

Example 14

[0936][2-(3-Methylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-14):

[0937] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 249-250° C.; ¹H NMR (DMSO) δ 2.06 (3H,s), 2.36 (3H, s), 5.31 (1H, s), 7.45 (2H, d), 7.48-7.58 (3H, m), 7.61(1H, d), 7.88 (1H, t), 8.68 (1H, d), 11.66 (1H, br s); IR (solid) 1617,1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1(M+H)⁺

Example 15

[0938][2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-15):

[0939] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 237-239° C.; ¹H NMR (DMSO) δ 2.07 (3H,s), 3.71 (3H, s), 5.35 (1H, s), 7.12 (1H, t), 7.23 (1H, d), 7.55 (1H,t), 7.60-7.67 (3H, m), 7.87 (1H, t), 8.66 (1H, d), 11.20 (1H, br s); IR(solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251,1224; MS 364.1 (M+H)⁺

Example 16

[0940][2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-16):

[0941] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 267-270° C.; ¹H NMR (DMSO) δ 2.05 (3H,s), 5.09 (1H, s), 7.57 (1H, t), 7.62-7.75 (4H, m), 7.90 (1H, t), 8.07(3H, t), 8.40 (1H, s), 8.66 (1H, d), 11.28 (1H, br s); IR (solid) 1624,1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M+H)⁺

Example 17

[0942][2-(2,6-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-17):

[0943] Prepared in a manner similar to the above described Method E toafford a pale brown solid, mp >300° C.; 1H NMR (DMSO) δ 2.11 (3H, s),5.49 (1H, s), 7.49 (1H, t), 7.59-7.67 (2H, m), 7.76 (2H, d), 7.81 (1H,d), 8.60 (1H, d), 10.60 (1H, s); IR (solid) 1618, 1599, 1565, 1533,1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0(M+H)⁺

Example 18

[0944] [2-(3,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-18):

[0945] Prepared in a manner similar to the above described Method E toafford a pale yellow solid, mp 268-272° C.; ¹H NMR (DMSO) δ 2.11 (3H,s), 5.47 (1H, s), 7.56 (1H, t), 7.68-7.72 (2H, m), 7.83 (2H, d), 7.88(1H, t), 8.05 (1H, d), 8.66 (1H, d); IR (solid) 1628, 1607, 1556, 1488,1436, 14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402.0 (M+H)⁺

Example 19

[0946][2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-19):

[0947] Prepared in a manner similar to the above described Method E toafford a pale grey solid, mp 192-196° C.; ¹H NMR (DMSO) δ 1.60 (3H, s),5.48 (1H, s), 7.44 (2H, m), 7.53 (1H, t), 7.69 (2H, d), 7.76 (2H, m),7.85 (1H, t), 8.64 (1H, d), 10.79 (1H, s); IR (solid) 1618, 1606, 1569,1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 (M+H)⁺

Example 20

[0948][2-(2-Aminophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-20):

[0949] Prepared in a manner similar to the above described Method E toafford a bright yellow solid, mp 257-259° C.; ¹H NMR (DMSO) δ 2.11-2.30(3H, 2×br s), 6.10 (1H, br s), 7.10-7.80 (7H, m), 8.60 (1H, br s), 9.80(1H, br s), 10.80 (1H, br s); IR (solid) 1623, 1591, 1567, 1538, 1496,1483, 1410, 1351

Example 21

[0950](5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine(IIa-21):

[0951] Prepared in a manner similar to the above described Method E toafford a yellow solid, mp 233-236° C.; ¹H NMR (DMSO) δ 0.89 (2H, d),0.98 (2H, d), 1.67 (1H, m), 5.48 (1H, s), 7.54 -7.73 (7H, m), 7.89 (1H,t), 8.68 (1H, d), 11.60 (1H, br S); IR (solid) 1629, 1606, 1577, 1546,1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360.3 (M+H)⁺

Example 22

[0952](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-22):

[0953] Prepared in a manner similar to the above described Method E toafford a white solid, mp 224-225° C.; ¹H NMR (DMSO) δ 0.52 (2H, m), 0.86(2H, m), 1.67 (1H, m), 3.86 (3H, s), 5.60 (1H, s), 7.45 (1H, t), 7.56(1H, d), 7.66 (1H, t), 7.76 (1H, t), 7.93 (1H, d), 8.10 (1H, d), 8.18(1H, s), 8.57 (1H, d), 10.48 (1H, br s), 12.07 (1H, br s); IR (solid)1724, 1617, 1593, 1567, 1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260,1218, 1169, 1128; MS 418.3 (M+H)⁺

Example 23

[0954](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-23):

[0955] Prepared in a manner similar to the above described Method E toafford a white solid, mp 241-243° C.; ¹H NMR (DMSO) δ 0.55-0.63 (2H, m),1.87-1.97 (1H, m), 1.67-1.79 (1H, m), 2.35 (3H, s), 5.72 (1H, s),7.30-7.60 (6H, m), 7.68-7.78 (1H,m), 8.50-8.60 (1H, d), 10.38 (1H, s),12.02 (1H, s); IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, 1344,1287, 1176, 758, 665,656; MS (M+H)⁺

Example 24

[0956](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-24):

[0957] Prepared in a manner similar to the above described Method E toafford a white solid, mp 232-234° C.; ¹H NMR (DMSO) δ 0.55-0.62 (2H, m),0.88-0.97 (2H, m), 1.70-1.80 (1H, m), 3.79 (3H, s), 5.79 (1H, s), 7.08(1H, d), 7.22-7.29 (2H, m), 7.40-7.50 (2H, m), 7.60 (1H, d), 7.79 (1H,t), 8.57 (1H, d), 10.40 (1H, s), 12.04 (1H, s); IR (solid) 3100, 1618,1592, 1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1001,969, 826, 761, 692, 667; MS (M+H)⁺

Example 25

[0958](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-25):

[0959] Prepared in a manner similar to the above described Method E toafford a white solid, mp 250-252° C.; ¹H NMR (DMSO) δ 0.54-0.60 (2H, m),0.83-0.91 (2H, m), 1.68-1.77 (1H, m), 3.79 (3H, s), 3.85 (3H, s), 5.79(1H, s), 7.10 (1H, d), 7.20-7.26 (2H, m), 7.45 (1H, t), 7.57 (1H, d),7.77 (1H, t), 8.55 (1H, d), 10.45 (1H, s), 12.04 (1H, m); IR (solid)1617, 1593, 1567, 1530, 1504, 1479, 1457, 1439, 1398, 1364, 1347, 1288,1269, 1250, 1232, 1181, 1169, 1138, 1037, 1020, 997, 972, 882, 846, 804,764, 750; MS (M+H)⁺

Example 26

[0960][2-(3-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-26):

[0961] Prepared from IIa-22 according to Method G to afford a yellowsolid, mp >300° C.; ¹H NMR (DMSO) δ 0.53 (2H, d), 0.86 (2H, d), 1.65(1H, m), 5.37 (1H, s), 7.55 (1H, t), 7.68 (1H, t), 7.81 (1H, d), 7.88(1H, t), 7.95 (1H, d), 8.15 (1H, d), 8.15 (1H, s), 8.71 (1H, d), 11.32(1H, br s); IR (solid) 1702, 1626, 1609, 1559, 1490, 1412, 1355, 1293,1222, 1170; MS 404.7(M+H)⁺

Example 27

[0962](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-ylsulfanyl)—quinazolin-4-yl]-amine(IIa-27):

[0963] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 285-288° C.; ¹H NMR (DMSO) δ 0.25 (2H, brs), 0.52 (2H, br s), 0.87 (1H, m), 5.54 (1H, br s), 7.42-7.77 (4H, m),8.00 (3H, m), 8.30 (1H, br s), 8.56 (1H, br d), 10.42 and 11.88 (1H,2×br s); IR (solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287,1240, 1216, 1167, 1158, 1142, 1128, 996, 965; MS 410.7 (M+H)⁺

Example 28

[0964](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,4-difluorophenylsulfanyl)-quinazolin-4-yl]-amine(IIa-28):

[0965] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 250-253° C.; ¹H NMR (DMSO) δ 0.61 (2H, m),0.91 (2H, m), 1.74 (1H, m), 5.67 (1H, m), 7.24-7.28 (1H, m), 7.44-7.48(3H, m), 7.53-7.81 (2H, brm), 8.55 (1H, m), 10.47 and 12.10 (1H, 2×brs); IR (solid) 1614, 1598, 1565, 1525, 1479, 1423, 1398, 1366, 1345,1285, 1267, 1243, 1213, 1168, 1143, 1114, 1026, 995, 968; MS 396.6(M+H)⁺

Example 29

[0966](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine(IIa-29):

[0967] Prepared in a manner similar to the above described Method F toafford a white solid, mp 244° C.; ¹H NMR (DMSO) δ 0.13 (2H,s), 0.45(2H,s), 0.79 (1H, s), 1.73 (4H, s), 2.42 (2H, s), 2.58 (2H, s), 5.28(1H, s), 7.58 (2H, d), 7.61 (2H, d), 7.97 (3H, d), 8.23 (1H, s), 8.56(1H, s), 11.63 (1H, s); IR (solid) 1594, 1561, 1514, 1477, 1423, 1333,1279, 1251, 990, 808, 744, 657, 651; MS 414.7(M+H)⁺

Example 30

[0968](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dichlorophenylsulfanyl)-quinazolin-4-yl]-amine(IIa-30):

[0969] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 250-252° C.; ¹H NMR (DMSO) δ 0.60 (2H, d),0.93 (2H, d), 1.70 (1H, m), 5.54 (1H, s), 7.47 (2H, m), 7.57 (1H, d),7.76 (1H, t), 7.86 (2H, d), 8.57 (1H, d), 10.48 (1H, s), 12.04 (1H, s);IR (solid) 1616, 1601, 1570, 1528, 1486, 1432, 1400, 1367, 1335, 1285,1246, 1210, 1159, 1146, 1051, 1033, 1021, 997; MS 428.6(M+H)⁺

Example 31

[0970][2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-31):

[0971] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 235-238° C.; ¹H NMR (DMSO) δ 0.58 (2H, d),0.92 (2H, d), 1.75 (1H, m), 5.71 (1H, s), 7.44 (1H, t), 7.50-7.63 (4H,m), 7.73 (1H, s), 7.75 (1H, t), 8.57 (1H, d), 10.46 (1H, s), 12.08 (1H,s); IR (solid) 1616, 1593, 1562, 1528, 1479, 1456, 1406, 1367, 1343,1286, 1244, 1216, 1176, 1067, 1051, 997; MS 394.7(M+H)⁺

Example 32

[0972][2-(2-Chlorophenylsulfanyl)—quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-32):

[0973] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 255-257° C.; 1H NMR (DMSO) δ 0.59 (2H, d),0.91 (2H, d), 1.71 (1H, m), 5.62 (1H, s), 7.45 (2H, m), 7.57 (1H, m),7.69 (1H, d), 7.75 (1H, t), 7.85 (1H, d), 8.56 (1H, d), 10.43 (1H, s),12.03 (1H, s); IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398,1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, 1030, 997; MS394.7(M+H)⁺

Example 33

[0974](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-33):

[0975] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 255-256° C.; ¹H NMR (DMSO) 6 0.56 (2H, m),0.90 (2H, m), 1.67 (1H, m), 2.26 and 2.29 (6H, 2×s), 5.75 (1H, br s),7.26 (1H, m), 7.35-7.55 (4H, m), 7.74 (1H, m), 8.54 (1H, br s), 10.44and 12.06 (2H, 2×br s); IR (solid) 1617, 1596, 1569, 1526, 1479, 1459,1404, 1366, 1343, 1287, 1243. 1218, 1167, 1145, 1017, 996, 966; MS388.3(M+H)⁺

Example 34

[0976][2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-34):

[0977] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 201-203° C.; ¹H NMR (DMSO) 8 0.44 (2H, m),0.71 (2H, m), 1.17 (1H, m), 5.72 (1H, m), 7.23 (2H, m), 7.51-7.81 (5H,m), 8.59 (1H, m), 10.59, 12.06 and 13.17 (3H, 3×br s); IR (solid) 1617,1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024,1010, 965; MS 400.2(M+H)⁺

Example 35

[0978](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine(IIa-35):

[0979] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 245-246° C.; ¹H NMR (DMSO) 6 0.47 (2H, brs), 0.80 (2H, br s), 1.62 (1H, m), 3.85 (3H, s), 5.69 (1H, br s), 7.46(1H, m), 7.58 (1H, m), 7.76-7.81 (3H, m), 8.02-8.05 (2H, m), 8.57 (1H,m), 10.48 and 12.11 (2H, 2×br s); IR (solid) 1721, 1712, 1616, 1596,1572, 1564, 1523, 1481, 1435, 1404, 1360, 1346, 1277, 1181, 1114, 1106,996, 971; MS 418.2(M+H)⁺

Example 36

[0980][2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-36):

[0981] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 239-241° C.; ¹H NMR (DMSO) δ 0.57 (2H, m),0.83 (2H, m), 1.69 (1H, m), 2.02 (3H, s), 5.73 (1H, br s), 7.41 (1H, m),7.53-7.57 (3H, m), 7.73-7.75 (3H, m), 8.54 (1H, m), 10.18, 10.39 and11.98 (3H, 3×br s); IR (solid) 1665, 1618, 1607, 1586, 1572, 1564, 1529,1482, 1387, 1343, 1320, 1287, 1243, 1221, 1162, 1005, 968; MS417.2(M+H)⁺

Example 37

[0982](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-l-ylsulfanyl)-quinazolin-4-yl]-amine(IIa-37):

[0983] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 271-273° C.; ¹H NMR (DMSO) δ 0.46-0.47(2H, m), 0.87-0.89 (2H, m), 1.57 (1H, m), 5.01 (1H, m), 7.42 (1H, m),7.52-7.54 (3H, m), 7.64 (1H, m), 7.75 (1H, m), 7.98 (1H, m), 8.06 (1H,m), 8.17 (1H, m), 8.28 (1H, m), 8.50 (1H, m), 10.29 (1H, br s), 11.84(1H, br s); IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362, 1343,1285, 1242, 1219, 1173, 998, 963; MS 410.2(M+H)⁺

Example 38

[0984][2-(4-Acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-38):

[0985] Prepared in a manner similar to the above described Method E toafford an white solid, mp 268-271° C.; ¹H NMR (DMSO) δ 2.02 (3H, s),2.09 (3H, s), 5.56 (1H, s), 7.40 (1H, t), 7.55 (3H, m), 7.75 (3H, d),8.55 (1H, d), 10.21 (1H, s), 10.40 (1H, s), 12.03 (1H, s); IR (solid)1662, 1620, 1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312,1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391.2(M+H)⁺

Example 39

[0986][2-(4-Methanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-39):

[0987] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 219-222° C.; ¹H NMR (DMSO) δ 2.15 (3H, s),2.61 (3H, s), 5.84 (1H, s), 6.91 (2H, d), 7.22 (2H, d), 7.36 (1H, s),7.52 (1H, d), 7.69 (1H, s), 8.53 (1H, d), 10.31 (1H, s), 11.96 (1H, S);IR (solid) 1621, 1602, 1584, 1567, 1528, 1486, 1351, 1287, 1253, 1207,1179, 1102, 1091, 983; MS 427.0(M+H)⁺

Example 40

[0988][2-(4-Acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-40):

[0989] Prepared in a manner similar to the above described Method E toafford a white solid, mp 291-293° C.; ¹H NMR (DMSO) δ 2.01 (3H, s), 2.09(3H, s), 3.87 (3H, s), 5.55 (1H, s), 6.96 (1H, s), 6.99 (1H, d), 7.55(2H, d), 7.73 (2H, d), 8.45 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.99(1H, s); IR (solid) ; MS 421.2(M+H)⁺

Example 41

[0990][2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-41):

[0991] Prepared in a manner similar to the above described Method E toafford a white solid, mp 262-264° C.; ¹H NMR (DMSO) δ 1.94 (2H, quint.),2.03 (3H, s), 2.09 (3H, s), 2.38 (4H, s), 2.45 (2H, t), 3.58 (4H, s),4.11 (2H, t), 5.60 (1H, s), 7.24 (1H, d), 7.30 (1H, t), 7.57 (2H, d),7.73 (2H, d), 8.07 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, brs); IR (solid) 3245, 3045, 2954, 2918, 2845, 1663, 1609, 1586, 1527,1468, 1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 ; MS534.4(M+H)⁺

Example 42

[0992][2-(4-Methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-42):

[0993] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 257-260° C.; ¹H NMR (DMSO) δ 1.95 (3H, s),3.89 (3H, s), 5.51 (1H, br s), 7.39 (1H, br s), 7.51 (1H, br s), 7.70(1H, br s), 7.81 (2H, d), 8.04 (2H, d), 8.51 (1H, br s), 10.48 (1H, brs), 12.03 (1H, br s); IR (solid) 1718, 1618, 1599, 1568, 1531, 1481,1434, 1395, 1362, 1342, 1286, 1247, 1216, 1156, 1116, 1018, 1003, 968 ;MS 392.2(M+H)⁺

Example 43

[0994][2-(4-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-43):

[0995] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 263-265° C.; ¹H NMR (DMSO) δ 1.98 (3H, s),5.50 (1H, s), 7.46 (1H, t), 7.60 (1H, d), 7.78 (3H, m), 8.02 (2H, d),8.58 (1H, d), 10.58 (1H, s), 12.50 (1H, br s); IR (solid) 1623, 1605,1574, 1560, 1533, 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131,1088, 1018; MS 378.2(M+H)⁺

Example 44

[0996][2-(4-Acetamidophenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-44):

[0997] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 247-249° C; ¹H NMR (DMSO) 1.99 (3H, s),2.10 (3H, s), 3.93 (3H, s), 5.40 (1H, s), 7.31 (1H, d), 7.38 (1H, t),7.57 (2H, d), 7.76 (2H, d), 8.11 (1H, d), 10.28 (1H, s), 10.61 (1H, s),12.11 (1H, br s); IR (solid) 3234, 3052, 2938, 1673, 1618, 1591, 1536,1481, 1459, 1390, 1372, 1345, 1317, 1267, 1249, 1158, 1058, 985, 830; MS421.2(M+H)⁺

Example 45

[0998][2-(4-Acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-45):

[0999] Prepared from IIa-74 according to Method I to afford an off-whitesolid, mp 153° C. (dec.); ¹H NMR (DMSO) δ 2.02 (3H, s), 2.09 (3H, s),2.29 (2H, quint.), 3.16 (2H, m), 3.36 (4H,m), 3.57 (4H, m), 4.11 (2H,m), 5.58 (1H, s), 7.22-7.29 (2H, m), 7.55 (2H, d), 7.76 (2H, d), 8.07(1H, d), 10.26 (1H, br s), 10.35 (1H, s), 12.06 (1H, br s); IR (solid)1673, 1614, 1591, 1532, 1486, 1391, 1336, 1254, 1109, 1063, 995; MS534.2(M+H)⁺

Example 46

[1000][2-(4-Bromophenylsulfanyl)quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-46):

[1001] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp >300° C.; ¹H NMR (DMSO) δ 2.15 (3H, s),5.63 (1H, br s), 7.44 (1H, m), 7.55-7.62 (3H, m), 7.69-7.77 (3H, m),8.56 (1H, m), 10.47 and 12.12 (2H, 2×br s); IR (solid) 1615, 1597, 1565,1525, 1478, 1396, 1362, 1339, 1285, 1218, 1158, 1034, 1009, 967; MS412.1/414.1(M+H)⁺

Example 47

[1002][2-(3-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-47):

[1003] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 280-281° C.; ¹H NMR (DMSO) δ 2.12 (3H, s),5.54 (1H, br s), 7.46 (1H, m), 7.55-7.68 (3H, m), 7.75-7.88 (3H, m),8.81 (1H, m), 10.49 and 12.11 (2H, 2×br s); IR (solid) 1617, 1600, 1567,1530, 1483, 1399, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005, 967;MS 412.2/414.2(M+H)⁺

Example 48

[1004](2-(4-Isopropanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(IIa-48):

[1005] Prepared in a manner similar to the above described Method E toafford a white solid, mp 294-297° C.; ¹H NMR (DMSO) δ 1.26 (6H, d), 2.13(3H, s), 5.75 (1H, s), 7.34 (2H, d), 7.41 (1H, t), 7.54 (1H, d), 7.59(2H, d), 7.73 (1H, t), 8.53 (1H, d), 10.16 (1H, s), 10.42 (1H, s), 12.07(1H, br s); IR (solid) 1613, 1593, 1560, 1530, 1482, 1384, 1364, 1346,1320, 1290, 1265, 1243, 1216, 1169, 1141, 1084, 1056, 1019, 999, 969,916; MS 455.2(M+H)⁺

Example 49

[1006][2-(4-Isobutyrylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine(IIa-49):

[1007] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 285-287° C.; ¹H NMR (DMSO) δ 1.12-1.13(6H, m), 1.99 (3H, s), 2.64 (1H, m), 5.52 (1H, br s), 7.41 (1H, m),7.54-7.57 (3H, m), 7.72-7.77 (3H, m), 8.54 (1H, m), 10.12, 10.41 and12.04 (3H, 3×br s); IR (solid) 1704, 1680, 1617, 1590, 1566, 1516, 1481,1395, 1358, 1341, 1286, 1247, 1214, 1155, 1052, 1032, 1006, 969; MS419.3(M+H)⁺

Example 50

[1008](5-Methyl-2H-pyrazol-3-yl)-[2-(4-propionylamino-phenylsulfanyl)-quinazolin-4-yl]-amine(IIa-50):

[1009] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 281-282° C.; ¹H NMR (DMSO) δ 1.11-1.13(3H, m), 1.98 (3H, s), 2.33 (2H, m), 5.51 (1H, br s), 7.41 (1H, m),7.55-7.57 (3H, m), 7.71-7.78 (3H, m), 8.54 (1H, m), 10.11, 10.41 and12.04 (3H, 3×br s); IR (solid) 1654, 1621, 1599, 1571, 1527, 1476, 1398,1358, 1341, 1286, 1244, 1216, 1155, 1006, 969; MS 405.3(M+H)⁺

Example 51

[1010][2-(4-cyclopropanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-51):

[1011] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 300-303° C.; 1H NMR (DMSO) δ 0.82-0.84(4H, m), 1.83 (1H, m), 2.01 (3H, S), 5.55 (1H, br s), 7.39-7.41 (2H, m),7.53-7.57 (2H, m), 7.72-7.77 (2H, m), 8.53-8.55 (2H, m), 10.40, 10.46and 12.03 (3H, 3×br s); IR (solid) 1664, 1614, 1591, 1560, 1526, 1480,1432, 1390, 1344, 1288, 1240, 1194, 1177, 1152, 997; MS 417.2(M+H)⁺

Example 52

[1012][2-(4-Acetamido-phenylsulfanyl)-8-hydroxyquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-52): tan solid, mp 258-259° C.; 1H NMR (DMSO) δ 1.99 (3H, s), 2.09(3H, s), 5.45 (1H, s), 7.10 (1H, d), 7.22 (1H, t), 7.57 (2H, d), 7.75(2H, d), 7.95 (1H, d), 9.35 (1H, s), 10.22 (1H, s), 10.26 (1H, s), 12.00(1H, br s); IR (solid) 3295, 3272, 3181, 3109, 1654, 1591, 1527, 1482,1459, 1386, 1368, 1314, 1268, 1141, 1077, 991, 814; MS 407.2(M+H)⁺

Example 53

[1013][2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-53):

[1014] Prepared in a manner similar to the above described Method E toafford a yellow solid; ¹H NMR (DMSO) δ 2.02 (3H, s), 2.09 (3H, s), 5.54(1H, s), 7.58 (2H, d), 7.75 (2H, d), 8.08 (1H, d), 8.22 (1H, s), 8.80(1H, d), 10.24 (1H, s), 10.85 (1H, s), 12.15 (1H, s); IR (solid); MS436.2(M+H)⁺

Example 54

[1015](5-Methyl-2H-pyrazol-3-yl)-{2-[4-(propane-1-sulfonylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-54):

[1016] Prepared in a manner similar to the above described Method E toafford a white solid, mp 272-273° C.; ¹H NMR (DMSO) δ 0.95 (3H, t), 1.71(2H, m), 2.13 (3H,s), 3.18 (2H, t), 5.70 (1H, s), 7.31 (2H, d), 7.41(1H, t), 7.52 (1H, d), 7.58 (1H, d), 7.73 (1H, t), 8.55 (1H, d), 10.16(1H, s), 10.42 (1H, s), 12.07 (1H, s); IR (solid) 1615, 1594, 1563,1530, 1481, 1389, 1362, 1346, 1325, 1291, 1245, 1147, 969; MS455.-2(M+H)⁺

Example 55

[1017][2-(4-Ethylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-55):

[1018] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 279-280° C.; ¹H NMR (DMSO) δ 1.28 (3H, t),2.19 (3H,s), 3.25 (2H, m), 5.76 (1H, s), 7.36 (2H, d), 7.48 (1H, t),7.53 (1H, d), 7.65 (1H, d), 7.80 (1H, t), 8.61 (1H, d), 10.23 (1H, s),10.49 (1H, s), 12.13 (1H, s); IR (solid) 1615, 1597, 1564, 1532, 1506,1485, 1455, 1388, 1361, 1347, 1323, 1294, 1218, 1150, 1033, 1016, 998,968, 918; MS 441.2(M+H)⁺

Example 56

[1019][2-(4-Acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-56):

[1020] Prepared from IIa-53 according to Method J to afford a yellowsolid; ¹H NMR (DMSO) δ 1.97 (3H, s), 2.11 (3H, s), 5.19 (1H, s),6.88-6.91 (2H, m), 7.65 (2H, d), 7.85 (2H, d), 8.44 (1H, d), 9.27 (1H,br s), 10.49 (1H, s), 11.38 (1H, s), 14.58 (1H, br s); IR (solid); MS422.2 (M+H)⁺

Example 57

[1021][2-(4-Isobutanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-57):

[1022] Prepared in a manner similar to the above described Method E toafford a white solid, mp 281-282° C.; ¹H NMR (DMSO) δ 0.95-0.97 (6H, m),2.00 (3H, s), 2.12 (1H, m), 2.23-2.25 (2H, m), 5.56 (1H, s), 7.41 (1H,m), 7.54-7.57 (3H, m), 7.72-7.78 (3H, m), 8.54 (1H, m), 10.14, 10.41 and12.03 (3H, 3×br s); IR (solid) 1737, 1658, 1618, 1599, 1566, 1530, 1483,1432, 1394, 1364, 1343, 1313, 1287, 1242, 1216, 1167, 1151, 1003, 967;MS 433.2(M+H)⁺

Example 58

[1023][2-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-58):

[1024] Prepared in a manner similar to the above described Method E toafford a white solid, mp 243-246° C.; ¹H NMR (DMSO) δ 1.50 (9H, s), 1.97(3H,s), 5.40 (1H, s), 7.07 (2H, br s), 7.36 (1H, br s), 7.47 (2H, d),7.58 (2H, d), 8.12 (1H, br s), 9.58 (1H, s), 11.24 (1H, br s); IR(solid) 1701, 1593, 1559, 1515, 1482, 1396, 1365, 1346, 1308, 1288,1237, 1154, 1051, 1020, 969; MS 449.2(M+H)⁺

Example 59

[1025][2-(4-Acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-59):

[1026] Prepared from IIa-53 according to Method K to afford an off-whitesolid, mp 264-265 ° C.; ¹H NMR (DMSO) δ 1.99 (3H, s), 2.09 (1H, s), 5.53(1H, s), 5.97 (2H, s), 6.47 (1H, s), 6.68 (1H, d), 7.52 (2H, d), 7.71(2H, d), 8.15 (1H, d), 9.83 (1H, br s), 10.19 (1H, s), 10.87 (1H, br s);IR (solid); MS 406.2(M+H)⁺

Example 60

[1027](5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-60):

[1028] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 266-267° C.; ¹H NMR (DMSO) δ 2.03 (3H, s),2.57 (4H, m), 3.23 (2H,s), 3.69 (4H, m), 5.58 (1H, s), 7.40 (1H, t),7.55-7.62 (3H, m), 7.75 (1H, t), 7.80 (2H, d ), 8.54 (1H, d), 10.02 (1H,s), 10.41 (1H, S), 12.03 (1H,s); IR (solid) 1686, 1598, 1564, 1533,1515, 1484, 1387, 1362, 1348, 1291, 1113, 868, 801, 773; MS 476.4(M+H)⁺

Example 61

[1029](5-Cycloprpyl-2H-pyrazol-3-yl)-[2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-amine(IIa-61):

[1030] Prepared in a manner similar to the above described Method E toafford a white solid, mp 235-238° C.; ¹H NMR (DMSO) δ 0.61 (2H, s), 0.92(2H, d), 1.82 (1H, br s), 2.98 (3H,s), 5.90 (1H, s), 7.23 (2H, d), 7.41(1H, t), 7.54 (3H, m), 7.72 (1H, t), 8.55 (1H, d), 10.16 (1H, br s),10.38 (1H, s), 11.99 (1H, s); IR (solid) 1621, 1605, 1573, 1532, 1494,1455, 1375, 1342, 1316, 1290, 1232, 1143, 1113, 985, 972; MS 453.3(M+H)⁺

Example 62

[1031][2-(4-Amino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-62):

[1032] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp >300° C.; ¹H NMR (DMSO) δ 2.16 (3H, s),5.58 (1H, s), 6.78 (2H,. d), 7.36 (2H, d), 7.64 (2H, m), 7.94 (1H, t),8.74 (1H, d), 11.82 (1H, br s); IR (solid) 1615, 1591, 1561, 1532, 1495,1480, 1387, 1363, 1344, 1288, 1244, 1148, 966; MS 349.2(M+H)⁺

Example 63

[1033][2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(2H-pyrazol-3-yl)amine(IIa-63):

[1034] Prepared in a manner similar to the above described Method E toafford a white solid, ¹H NMR (DMSO) δ 2.11 (3H, s), 5.93 (1H, s),7.31-7.68 (8H, m), 8.54 (1H, s), 10.17 (1H, s), 10.54 (1H, s), 12.38(1H, s); IR (solid); MS 377.4(M+H)⁺

Example 64

[1035](5-Methyl-2H-pyrazol-3-yl)-{2-[4-(4-morpholin-4-yl-butyrylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-64):

[1036] Prepared in a manner similar to the above described Method E toafford a white solid, mp 240-243° C.; ¹H NMR (DMSO) δ 1.77 (2H, m), 2.00(3H, s), 2.31-2.38 (8H, m), 3.57 (4H, m), 5.54 (1H, s), 7.39-7.76 (7H,m), 8.53 (1H, br m), 10.15 (1H, s), 10.41 (1H, s), 12.00 (1H, br s); IR(solid); MS 504.3(M+H)⁺

Example 65

[1037](5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-amine(IIa-65):

[1038] Prepared in a manner similar to the above described Method E toafford a white solid, mp 246-248° C.; ¹H NMR (DMSO) δ 1.97 (3H, s), 2.43(4H, br s), 3.30 (2H, s), 3.42 (2H, m), 3.58 (4H, br s), 5.52 (1H, s),7.43 (1H, t), 7.55 (1H, d), 7.76 (3H, m), 7.97 (2H, d), 8.56 (2H, m),10.45 (1H, s), 12.05 (1H, br s); IR (solid) 1637, 1618, 1596, 1568,1530, 1484, 1396, 1362, 1343, 1286, 1247, 1216, 1159, 1116, 1006, 967;MS 490.3(M+H)⁺

Example 66

[1039][8-Methoxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-66):

[1040] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 275-277° C.; ¹H NMR (DMSO) δ 2.10 (3H, s),3.07 (3H, s), 3.89 (3H, s), 5.58 (1H, s), 7.24 (1H, d), 7.26-7.36 (3H,m), 7.60 (2H, d), 8.07 (1H, d), 10.13 (1H, s), 11.26 (1H, s), 12.03 (1H,s); IR (solid) 3379, 1622, 1595, 1531, 1481, 1467, 1344, 1326, 1271,1248, 1143, 1061, 993, 975, 924, 829; MS 457.2(M+H)⁺

Example 67

[1041]{2-[4-(2-Dimethylamino-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-67):

[1042] Prepared in a manner similar to the above described Method E toafford a white solid, mp 192-193° C.; ¹H NMR (DMSO) δ 1.99 (3H, s), 2.20(6H,s), 2.42 (2H, t), 3.40 (2H, q), 5.56 (1H, s), 7.43 (1H, t), 7.57(1H, d), 7.77 (3H, m), 7.92 (2H, d), 8.56 (2H, m), 10.44 (1H, s), 12.04(1H, br s); IR (solid) 1650, 1618, 1593, 1561, 1525, 1481, 1419, 1395,1361, 1337, 1287, 1247, 1214, 1165, 1004, 969; MS 448.3(M+H)⁺

Example 68

[1043]{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-68):

[1044] Prepared in a manner similar to the above described Method E toafford a white solid, mp 241-243° C.; ¹H NMR (DMSO) δ 2.00 (3H, s), 2.33(6H, s), 3.14 (2H, s), 5.60 (1H, s), 7.40 (1H, t), 7.58 (3H, m ), 7.77(1H, t ), 7.76 (2H, d), 8.58 (1H, d), 10.04 (1H, s), 10.42 (1H, s),11.99 (1H, s).; IR (solid) 1707, 1617, 1601, 1571, 1509, 1485, 1420,1397, 1365, 1304, 1290, 1243, 1215, 1161, 970, 847, 813, 765, 716, 683,656; MS 434.3(M+H)⁺

Example 69

[1045][8-Hydroxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-69):

[1046] pale green solid, mp 291-293° C.; ¹H NMR (DMSO) δ 2.10 (3H, s),3.09 (3H, s), 5.57 (1H, s), 7.11 (1H, d), 7.24 (1H, t), 7.31 (2H, d),7.62 (2H, d), 7.96 (1H, d), 9.32 (1H, s), 10.16 (1H, s), 11.28 (1H, s),12.02 (1H, s); IR (solid) 3256, 1596, 1531, 1460, 1392, 1317, 1334,1296, 1267, 1146, 993, 968, 931, 824; MS 443.2(M+H)⁺

Example 70

[1047] {2-[4-(3-Dimethylamino-propylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-70):

[1048] Prepared in a manner similar to the above described Method E toafford a pink solid, mp 210-213° C.; ¹H NMR (DMSO) δ 1.48 (2H, m), 2.01(3H, s), 2.24 (6H,s), 2.38 (2H, br s), 2.93 (2H, s), 5.57 (1H, s), 7.48(1H, t), 7.62 (1H, d), 7.80 (3H, m), 8.02 (2H, d), 8.61 (1H, d) 8.74(1H, s), 10.50 (1H, s), 12.15 (1H, br s); IR (solid) 1682, 1618, 1595,1567, 1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006,969; MS 462.3(M+H)⁺

Example 71

[1049]{2-[4-(3-Dimethylamino-propionylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-71):

[1050] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 280° C. (dec.); ¹H NMR (DMSO) δ 2.09 (3H,s), 2.60 (6H, s), 2.93 (2H, m), 3.10 (2H, m), 5.64 (1H, s), 7.47 (1H,t), 7.59-7.70 (3H, m), 7.80-7.87 (3H, m), 8.61 (1H, d), 10.47 (1H, s),10.48 (1H, S), 12.15 (1H, s).; IR (solid) 1670, 1619, 1598, 1586, 1571,1534, 1515, 1481, 1397, 1364, 1348, 1286, 1178, 1162, 764; MS448.4(M+H)^(+c)Example 72

[1051][2-(4-Acetamido-phenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIa-72):

[1052] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 265-268° C.; ¹H NMR (DMSO) δ 0.49-0.56(2H, m), 0.79-0.83 (2H, m), 1.55-1.70 (1H, m), 2.06 (3H, s), 3.89 (3H,s), 5.61 (1H, s), 7.25 (1H, d), 7.33 (1H, t), 7.56 (2H, d), 7.74 (2H,d), 8.07 (1H, d), 10.17 (1H, s), 10.26 (1H, s), 11.94 (1H, br s); IR(solid) 3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335,1254, 1160, 1131, 1071, 1011, 984, 869, 815; MS 447.4(M+H)⁺

Example 73

[1053][2-(4-Acetamidophenylsulfanyl)-8-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-73):

[1054] Prepared in a manner similar to the above described Method E toafford an off-white solid, mp 170-172° C.; ¹H NMR (DMSO) δ 1.91 (2H,quint.), 2.03 (3H, s), 2.09 (3H, s), 2.17 (6H, s), 2.40 (2H, t), 4.10(2H, t), 5.59 (1H, s), 7.23 (1H, d), 7.30 (1H, t), 7.57 (2H, d), 7.73(2H, d), 8.06 (1H, d), 10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, br s);IR (solid) 3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371, 1338,1316, 1253, 1161, 1137, 1062, 1038, 994, 958, 823; MS 492.4(M+H)⁺

Example 74

[1055][2-(4-Acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-74):

[1056] Prepared from IIa-40 according to Method H to afford an off-whitesolid, mp 246-248° C.; ¹H NMR (DMSO) δ 2.00 (3H, s), 2.08 (3H, s), 5.52(1H, s), 6.78 (1H, s), 6.87 (1H, d), 7.54 (2H, d), 7.72 (2H, d), 8.37(1H, d), 10.06 (1H, s), 10.17 (1H, s), 10.37 (1H, s), 11.95 (1H, br s);IR (solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420, 1389, 1359, 1298,1223, 1176, 1148, 1087, 1026, 1010, 965; MS 407.4(M+H)⁺

Example 75

[1057][2-(4-Acetamidophenylsulfanyl)-7-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-75):

[1058] Prepared in a manner similar to the above described Method I toafford an off-white solid, mp 249-250° C.; ¹H NMR (DMSO) δ 1.90 (2H,quint.), 2.01 (3H, s), 2.09 (3H, s), 2.19 (6H, s), 2.42 (2H, m), 4.12(2H, t), 5.55 (1H, s), 6.93 (1H, s), 6.98 (1H, d), 7.55 (2H, d), 7.73(2H, d), 8.43 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.98 (1H, br s);IR (solid) 3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420, 1394,1344, 1320, 1292, 1263, 1222, 1168, 1048, 1034, 1005, 967, 864, 844; MS492.4(M+H)⁺

Example 76

[1059](2-{4-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-phenylsulfanyl}-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-76):

[1060] Prepared in a manner similar to the above described Method E toafford a white solid, mp 228-229° C. (dec.); ¹H NMR (DMSO) δ 1.37 (3H,S), 1.40 (3H, s), 2.02+2.03 (3H, 2×s), 2.88+2.90 (3H, 2×s), 4.01+4.02(2H, 2×s), 5.52+5.57 (1H, 2×s), 7.47 (1H, t), 7.55-7.63 (3H, m),7.75-7.80 (3H, m), 8.60 (1H,d), 10.28+10.30 (1H, 2×s), 10.45 (1H, s),12.08 (1H, s).; IR (solid) 1698, 1683, 1653, 1617, 1594, 1559, 1538,1532, 1507, 1488, 1457, 1418, 1397, 1364, 1346, 1307, 1287, 1246, 1151,842, 827, 759; MS 520.4 (M+H)⁺

Example 77

[1061]{2-[4-(2-Methylamino-acetylamino)-phenylsulfanyl]-quinazoli-n-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-77):

[1062] Prepared in a manner similar to the above described Method E toafford a white solid, mp 242-244° C.; ¹H NMR (DMSO) δ 2.01 (3H, s), 2.34(3H, s), 3.32 (2H, s), 5.58 (1H, s), 7.45 (1H, t), 7.50-7.60 (3H, m),7.75 (1H, t), 7.80 (2H, d), 8.55 (1H, d), 10.10 (1H, br s), 10.42 (1H,s), 12.02 (1H, s); IR (solid) 1674, 1619, 1598, 1570, 1525, 1483, 1417,1363, 1345, 1298, 1285, 1247, 1160, 966, 827, 804, 784, 763, 712, 670,653; MS 420.4 (M+H)⁺

Example 78

[1063][2-(4-Acetamidophenylsulfanyl)-8-fluoro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-78):

[1064] Prepared in a manner similar to the above described Method E toafford a white solid, mp 257-259° C.; ¹H NMR (DMSO) δ 2.01 (3H, s), 2.09(3H, s), 5.49 (1H, s), 7.42 (1H, t), 7.57-7.68 (3H, m), 7.75 (2H, d),8.40 (1H, d), 10.28 (1H, s), 10.75 (1H, s); ¹⁹F NMR (DMSO) δ-127.3; IR(solid) 1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456, 1434,1395, 1366, 1332, 1315, 1289, 1254, 1242, 1032, 838, 829, 808, 744; MS409.4(M+H)⁺

Example 79

[1065] (1H-Indazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine(IIa-79):

[1066] Prepared in a manner similar to the above described Method E toafford a white solid. ¹H NMR (DMSO) δ 7.07 (m, 3H), 7.19 (t, 1H), 7.37(d, 2H), 7.39 (t, 1H), 7.52 (dd, 1H), 7.54 (t, 1H), 7.55 (d, 1H), 7.56(t, 1H), 7.83 (t, 1H), 8.53 (d, 1H), 10.71 (s, 1H), 12.85 (s, 1H); MS370.1 (M+H)⁺

Example 80

[1067]{2-[(2-Hydroxyethyl)phenylamino]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-1):

[1068] Prepared in a manner similar to the above described Method A toafford a brown solid, mp 217° C.; ¹H NMR (DMSO) δ 1.99 (3H, s), 3.69(2H, t), 4.05 (2H, t), 5.00 (1H, br s), 5.53 (1H, br s), 7.09 (1H, m),7.25-7.40 (4H, m), 7.40-7.48 (2H, m), 7.54 (1H, m), 8.34 (1H, m), 10.07(1H, s), 11.67 (1H, br s); IR (solid) 3395, 3155, 3052, 2934, 1623,1598, 1577, 1475, 1434, 1393; MS 361.2 (M+H)⁺

Example 81

[1069][2-(Methylphenylamino)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-2):

[1070] Prepared in a manner similar to the above described Method A toafford a white solid, mp 154-156° C.; ¹H NMR (DMSO) δ 2.03(3H, s),3.51(3H, s), 5.70(1H, s), 7.13(1H, m), 7.36-7.25(3H, m), 7.48-7.37 (3H,m), 7.58 (1H, m), 8.38 (1H, d), 9.98(1H, s), 11.91 (1H s); IR (solid)1621, 1598, 1578, 1540, 1494, 1473, 1398, 1374; MS 331.0 (M+H)⁺

Example 82

[1071](5-methyl-2H-pyrazol-3-yl)-{2-[N-methyl-N-(pyridin-3-ylmethyl)amino]-quinazolin-4-yl}-amine(IIc-3):

[1072] Prepared in a manner similar to the above described Method A toafford a yellow solid, mp 177° C.; ¹H NMR(DMSO) δ 0.45 (2H, s), 0.84(2H, s), 1.80 (1H, s), 3.16 (3H, s), 4.93 (2H, s), 6.18 (1H, br s), 7.10(1H, t), 7.34 (2H, s), 7.55 (1H, t), 7.64 (1H, s), 8.36 (1H, d), 8.45(1H, s), 8.52 (1H, s), 10.03 (1H, s), 12.17 (1H, s); IR (solid) 3104,2995, 2936, 1618, 1591, 1559, 1541, 1518, 1477, 1409, 1386, 1350, 1300,1018, 991, 873, 827; MS 372.3 (M+H)⁺

Example 83

[1073] (5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl)-amine(IIc-4):

[1074] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO @60° C.) δ 2.27(3H, s), 6.47(1H, brs), 6.92(1H, m), 7.31(3H, m), 7.53(1H, m), 7.70 (1H, m), 7.91 (2H, m),8.37 (2H, d), 9.16 (1H, br s), 10.05 (1H, br s), 12.15 (1H, br s); IR(solid) 1623, 1601, 1573, 1541, 1478; MS 317.0 (M+H)⁺

Example 84

[1075] (2-Benzylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-5):

[1076] Prepared in a manner similar to the above described Method A toafford a white solid, mp 225-227° C.; ¹H NMR (DMSO) δ 2.20 (3H, s),4.62(2H, d), 7.18 (1H, s), 7.43-7.60(8H, m), 8.22 (1H, s), 9.99 (1H, brs), 12.05 (1H, br s); IR (solid) 1630, 1609, 1578, 1538, 1511; MS 331.0(M+H)⁺

Example 85

[1077](2-Cyclohexylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-6):

[1078] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 280° C. (dec.); 1H NMR (DMSO) δ1.11-1.44(5H, m), 1.56 (1H, m), 1.71(2H, m), 1.92 (2H, m), 2.26(3H, s),3.75(1H, s), 6.63 (1H, br s), 7.04 (1H, s), 7.28 (1H, s), 7.51(1H, m),8.26(1H, s), 9.97(1H, br s), 12.08(1H, br s), 12.75(1H, br s); IR(solid) 2927, 2853, 1619, 1596, 1569, 1522, 1482; MS 323.0 (M+H)⁺

Example 86

[1079][2-(2,3-Dihydrobenzo[1,4]dioxin-6-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-7):

[1080] Prepared in a manner similar to the above described Method A toafford an off-green solid, mp >250° C.; ¹H NMR (DMSO) δ 2.23 (3H, s),4.15 (4H, m), 6.32 (1H, br s), 6.76 (1H, d), 7.16 (1H, t), 7.22 (1H,dd), 7.39 (1H, d), 7.57 (1H, t), 7.66 (1H, s), 8.34 (1H, d), 9.07 (1H,br s), 10.20 (1H, br s), 12.15 (1H, br s); IR (solid) 3445, 3045, 2968,2927, 2868, 1618, 1595, 1577, 1559, 1509, 1441, 1377, 1073; MS 375.1(M+H)⁺

Example 87

[1081](2-Cyclohexylmethylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-8):

[1082] Prepared in a manner similar to the above described Method A toafford a white solid, mp 211° C.; ¹H NMR (DMSO) δ 0.85-1.30 (5H, m),1.50-1.85 (6H, m), 2.22 (3H, s), 3.19 (2H, s), 6.50-7.00 (1H, br s),7.06 (1H, br s), 7.29 (1H, br s), 7.51 (1H, t), 8.26 (1H, br s), 9.97(1H, br s), 12.04 (1H, br s), 12.75 (1H, br s); IR (solid) 3333, 2927,2850, 2831, 1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 988; MS337.4 (M+H)⁺

Example 88

[1083][2-(1H-Indazol-6-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-9):

[1084] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp >250° C.; ¹H NMR (DMSO) δ 2.24 (3H, s),5.93 and 6.89 (1H, 2×br s), 7.05-8.15 (6H, m), 8.25-8.90 (2H, m), 9.25and 9.97 (1H, 2×br s), 10.11 and 10.57 (1H, 2×br s), 12.15 and 12.80(2H, 2×br s); IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467;MS 357.1 (M+H)⁺

Example 89

[1085](5-Methyl-2H-pyrazol-3-yl)-[2-(pyridin-3-ylmethylamino)-quinazolin-4-yl]-amine(IIc-10):

[1086] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 218° C.; ¹H NMR (DMSO) δ 2.20 (3H, s),4.59 (2H, s), 6.30 (1H, br s), 7.10 (1H, s), 7.33 (2H, s), 7.54 (1H, s),7.78 (1H, s), 8.31 (1H, s), 8.43 (1H, s), 8.61 (1H, s), 10.0 (1H, br s),12.15 (1H, br s); IR (solid) 3308, 2945, 2919, 2858, 1623, 1593, 1577,1552, 1501, 1475, 1449, 1383; MS 332.1-(M+H)⁺

Example 90

[1087][2-(3-Chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-11):

[1088] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp >250° C., ¹H NMR (DMSO) δ 2.29 (3H, s),5.30-6.98 (1H, m), 6.96 (1H, s), 7.28 (2H, s), 7.51 (1H, s), 7.67 (1H,s), 7.77 (1H, s), 8.23 (1H, s), 8.46 (1H, s), 9.35 and 10.00 (1H, 2×brs), 10.14 and 10.64 (1H, 2×br s), 12.20 and 12.82 (1H, 2×br s); IR(solid) 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, 1472,1440, 1403, 1372; MS 351.1 (M+H)⁺

Example 91

[1089][2-(4-Chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-12):

[1090] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp >250° C.; ¹H NMR (DMSO) δ 2.27 (3H, s),5.20-6.80 (1H, m), 7.26 (1H, s), 7.33 (2H, s), 7.51 (1H, s), 7.66 (1H,s), 7.99 (2H, d), 8.42 (1H, s), 9.29 and 9.93 (1H, 2×br s), 10.13 and10.55 (1H, 2×br s), 12.19 and 12.81 (1H, 2×br s); IR (solid) 3439, 3057,2957, 1618, 1600, 1586, 1572, 1550, 1504, 1486, 1431, 1413, 1367; MS351.1 (M+H)⁺

Example 92

[1091][2-(4-Fluorobenzylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-13):

[1092] Prepared in a manner similar to the above described Method A toafford a white solid, mp 216° C.; ¹H NMR (DMSO) δ 2.20 (3H, s), 4.56(2H, d), 6.30 (1H, br s), 7.05-7.20 (3H, m), 7.31 (1H, d), 7.42 (2H, S),7.54 (1H, t), 8.32 (1H, s), 10.01 and 10.34 (1H, 2×br s), 12.09 and12.75 (1H, 2×br s); IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508,1367; MS 349.3 (M+H)⁺

Example 93

[1093]{2-[2-(2-Hydroxyethyl)phenylamino]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-14):

[1094] Prepared in a manner similar to the above described Method A toafford a white solid, mp 222° C.; ¹H NMR (DMSO) δ 2.09 (3H, s), 2.80(2H, t), 3.61 (2H, t), 4.87 (1H, br s), 5.85 (1H, br s), 7.30-7.53 (5H,m), 7.63 (1H, d), 7.86 (1H, t), 8.68 (1H, d), 10.11 (1H, br s), 11.55(1H, br s), 12.49 (1H, br s), 13.50 (1H, br s); IR (solid) 3193, 3171,3111, 3084, 1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3(M+H)⁺

Example 94

[1095][2-(4-cyanomethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-15):

[1096] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp >250° C.; ¹H NMR (DMSO) 2.23 (3H, s), 4.09(2H, s), 6.28 (1H, br s), 7.41 (2H, d), 7.48 (1H, t), 7.57-7.63 (3H, m),7.87 (1H, t), 10.70 (1H, s), 11.56 (1H, s), 12.63 (1H, br s), 13.25 (1H,br s); IR (solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513, 1481,1413, 1336, 1158, 999; MS 356.2 (M+H)⁺

Example 95

[1097][2-(3-Hydroxymethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-16):

[1098] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp >250° C.; ¹H NMR (DMSO) δ 2.20 (3H, s),4.53 (2H, s), 5.22 (1H, br s), 6.31 (1H, br s), 7.24 (1H, d), 7.33-7.53(4H, m), 7.61 (1H, d), 7.86 (1H, t), 8.67 (1H, d), 10.61 (1H, br s),11.52 (1H, br s), 12.59 (1H, br s), 13.10 (1H, br s); IR (solid) 3401,3209, 3108, 3071, 2975, 2916, 1632, 1609, 1595, 1554, 1485, 1421, 1371,1348, 1046, 1005, 813; MS 347.3 (M+H)⁺

Example 96

[1099][2-(3-Hydroxyphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-17):

[1100] Prepared in a manner similar to the above described Method A toafford a white solid, mp >250° C.; ¹H NMR (DMSO) δ 2.22 (3H, s), 6.42(1H, br s), 6.72 (1H, d), 6.97 (2H, s), 7.21 (1H, t), 7.47 (1H, t), 7.60(1H, d), 7.85 (1H, t), 8.67 (1H, d), 9.76 (1H, s), 10.53 (1H, s), 11.53(1H, s), 12.58 (1H, br s), 12.99 (1H, br s); IR (solid) 3354, 3027,2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332, 1154, 1004; MS333.2 (M+H)⁺Example 97

[1101](5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl)-amine(IIc-18):

[1102] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 234° C.; ¹H NMR (DMSO) δ 0.74 (2H, s),0.92 (2H, s), 1.91 (1H, s), 5.83 and 6.54 (1H, 2×br s), 6.94 (1H, t),7.30 (3H, m), 7.50 (1H, s), 7.65 (1H, s), 7.91 (2H, d), 8.27 (1H, s),9.13 and 9.77 (1H, 2×br s), 10.07 and 10.52 (1H, 2×br s), 12.19 and12.82 (1H, 2×br s); IR (solid) 3443, 1622, 1595, 1577, 1554, 1486, 1449,1413, 1376, 1340, 1235, 1171, 988, 806; MS 343.2 (M+H)⁺

Example 98

[1103](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylamino)-quinazolin-4-yl]-amine(IIc-19):

[1104] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 117° C.; ¹H NMR (DMSO) δ 0.72 (2H, s),0.92 (2H, s), 1.90 (1H, m), 2.32 (3H, s), 6.20 (1H, br s), 6.80 (1H, d),7.20 (1H, t), 7.27 (1H, br s), 7.51 (1H, br s), 7.55-7.85 (3H, m), 8.43(1H, br s), 9.50 (1H, br s), 10.44 (1H, s), 12.55 (1H, br s); IR (solid)3303, 1618, 1581, 1554, 1536, 1495, 1472, 1436, 1413, 1372, 1336, 1240,990; MS 357.4 (M+H)⁺

Example 99

[1105](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(6-methoxypyridin-3-ylamino)-quinazolin-4-yl]-amine(IIc-20):

[1106] Prepared in a manner similar to the above described Method A toafford a pink solid, mp 120° C.; ¹H NMR (DMSO) δ 0.72 (2H, s), 0.91 (2H,s), 1.89 (1H, m), 3.85 (3H, s), 6.20 (1H, br s), 6.82 (1H, d), 7.25 (1H,s), 7.48 (1H, m), 7.66 (1H, t), 8.13 (1H, br s), 8.42 (1H, br s), 8.61(1H, br s), 9.50 (1H, br s), 10.48(1H, br s), 12.55 (1H, br s); IR(solid) 3457, 3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363,1272, 1235, 1035, 985, 821; MS 374.2 (M+H)⁺

Example 100

[1107](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-5-ylamino)-quinazolin-4-yl]-amine(IIc-21):

[1108] Prepared in a manner similar to the above described Method A toafford a pale brown solid, mp 199-204° C.; ¹H NMR (DMSO) δ 0.69 (2H, brs), 0.91 (2H, br s), 1.90 (1H, m), 2.02 (2H, m), 2.68 (1H, m), 2.83 (3H,m), 6.46 (1H, br s), 7.18 (1H, d), 7.26 (1H, br s), 7.50 (1H, d), 7.67(1H, t), 7.75 (1H, br s), 8.45 (1H, br s), 9.70 (1H, br s), 10.60 (1H,br s), 12.30 and 12.80 (1H, 2×br s); IR (solid) 1621, 1601, 1572, 1552,1495, 1474, 1439, 1425, 1408, 1382, 1363, 1319, 1267; MS 383.3 (M+H)⁺

Example 101

[1109](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1H-indol-6-ylamino)-quinazolin-4-yl]-amine(IIc-22):

[1110] Prepared in a manner similar to the above described Method A toafford a dark brown solid, mp >300° C.; ¹H NMR (DMSO) δ 0.69 (2H, br s),0.89 (2H, br s), 1.88 (1H, m), 5.77 and 6.74 (1H, 2×br s), 6.35 (1H, s),7.22 (3H, br s), 7.45 (2H, d), 7.65 (1H, s), 8.35 (2H, br s), 8.86, 9.70and 10.01 (1H, 3×br s), 10.49, 12.12 and 12.84 (1H, 3×br s), 10.94 (s,1H); IR (solid) 1623, 1603, 1571, 1549, 1495, 1477, 1460, 1419, 1383,1336, 1264, 1250, 1238; MS 382.4 (M+H)⁺

Example 102

[1111][2-(4-Acetamido-3-methylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-23):

[1112] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp >188° C. (dec.); ¹H NMR (DMSO) δ 0.72 (2H,br s), 0.94 (2H, br s), 1.92 (1H, m), 2.03 (3H, s), 2.19 (3H, s), 5.80and 6.69 (1H, 2×br s), 7.22 (2H, br s), 7.49 (1H, br s), 7.70 (3H, m),8.35 (1H, br s), 9.01, 9.59 and 10.01 (1H, 3×br s), 9.19 (1H, s), 10.53,12.16 and 12.81 (1H, 3×br s); IR (solid) 1637, 1624, 1578, 1542, 1502,1474, 1428, 1403, 1343, 1320, 1307, 1250; MS 414.4 (M+H)⁺

Example 103

[1113][2-(4-Chloro-3-methylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-24):

[1114] Prepared in a manner similar to the above described Method A toafford a pale brown solid, mp 244-246° C.; ¹H NMR (DMSO) δ 0.69 (2H, brs), 0.94 (2H, br s), 1.91 (1H, m), 2.32 (3H, s), 5.89 and 6.63 (1H, 2×brs), 7.28 (2H, m), 7.49 (1H, m), 7.65 (1H, m), 7.80 (1H, br s), 7.86 (1H,s), 8.40 (1H, br s), 9.17, 9.81 and 10.06 (1H, 3×br s), 10.58, 12.19 and12.78 (1H, 3×br s); IR (solid) 1615, 1578, 1549, 1475, 1419, 1397, 1365,1331, 1296, 1261, 1238, 1187, 1139; MS 391.4 (M+H)⁺

Example 104

[1115](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-ethylphenylamino)-quinazolin-4-yl]-amine(IIc-25):

[1116] Prepared in a manner similar to the above described Method A toafford a pale brown solid, mp 250-251° C.; ¹H NMR (DMSO) δ 0.72 (2H, brs), 0.91 (2H, br s), 1.19 (3H, t), 1.91 (1H, m), 2.58 (2H, q), 5.81 and6.64 (1H, 2×br s), 7.15 (2H, d), 7.22 (1H, s), 7.47 (1H, s), 7.64 (1H,s), 7.78 (2H, s), 8.36 (1H, br s), 9.03, 9.66 and 10.05 (1H, 3×br s),10.49, 12.20 and 12.80 (1H, 3×br s); IR (solid) 1603, 1574, 1546, 1509,1497, 1474, 1439, 1417, 1386; MS 371.5 (M+H)⁺

Example 105

[1117](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-propylphenylamino)-quinazolin-4-yl]-amine(IIc-26):

[1118] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 255-256° C.; ¹H NMR (DMSO) δ 0.72 (2H, brs), 0.91 (5H, t), 1.60 (2H, m), 1.90 (1H, m), 2.58 (2H, q), 5.81 and6.63 (1H, 2×br s), 7.12 (2H, d), 7.21 (1H, s), 7.47 (1H, s), 7.63 (1H,s), 7.77 (2H, s), 8.36 (1H, br s), 9.01, 9.70 and 10.11 (1H, 3×br s),10.51, 12.17 and 12.80 (1H, 3×br s); IR (solid) 1595, 1571, 1545, 1499,1477, 1442, 1413, 1388; MS 385.6 (M+H)⁺

Example 106

[1119](5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(2-hydroxyethyl)phenylamino]-quinazolin-4-yl}-amine(IIc-27):

[1120] Prepared in a manner similar to the above described Method A toafford a pale brown solid, mp 255-256° C.; ¹H NMR (DMSO) δ 0.73 (2H, brs), 0.91 (5H, t), 1.90 (1H, m), 2.69 (2H, t), 3.60 (2H, q), 4.62 (1H,t), 5.81 and 6.65 (1H, 2×br s), 7.15 (2H, d), 7.22 (1H, s), 7.46 (1H,s), 7.63 (1H, s), 7.77 (2H, s), 8.36 (1H, br s), 9.05, 9.69 and 10.02(1H, 3×br s), 10.52, 12.17 and 12.79 (1H, 3×br s); IR (solid) 1632,1569, 1546, 1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 (M+H)⁺

Example 107

[1121](5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenetylamino-quinazolin-4-yl)-amine(IIc-28):

[1122] Prepared in a manner similar to the above described Method A toafford a white solid, mp >250° C.; ¹H NMR (DMSO) δ 0.66 (2H, m), 0.84(2H, m), 1.83 (1H, m), 2.90 (2H, t), 3.56 (2H, m), 6.29 (1H, br s), 7.01(1H, t), 7.12-7.38 (6H, m), 7.48 (1H, t), 8.42 (1H, s), 10.91 (1H, brs), 13.11 (1H, br s); IR (solid) 2922, 1650, 1627, 1577, 1550, 1500,1482, 1395, 1368, 1004, 832; MS 371.3 (M+H)⁺

Example 108

[1123][2-(2-Cyclohexylethylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-29):

[1124] Prepared in a manner similar to the above described Method A toafford a white solid, mp >250° C.; ¹H NMR (DMSO) δ 0.70 (2H, s),0.80-1.00 (4H, m), 1.05-1.30 (4H, m), 1.30-1.50 (3H, m), 1.55-1.80 (5H,m), 1.87 (1H, s), 5.40-6.70 (2H, br s), 7.04 (1H, s), 7.25 (1H, s), 7.49(1H, s), 8.25 (1H, s), 10.06 (1H, br s), 11.93 (1H, br s); IR (solid)3448, 2920, 2852, 1618, 1600, 1568, 1550, 1486, 1418, 1395, 1367, 1258,1008, 985; MS 377.4 (M+H)⁺

Example 109

[1125][2-(4-Carboxymethoxyphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-30):

[1126] Prepared in a manner similar to the above described Method A toafford a yellow solid, mp >250° C.; ¹H NMR (DMSO) 0.72 (2H, m), 0.91(2H, m), 1.90 (1H, m), 4.62 (2H, s), 6.24 (1H, s), 6.88 (2H, s), 7.21(1H, m), 7.45 (1H, m), 7.62 (1H, m), 7.78 (2H, m), 8.35 (1H, m), 9.31(1H, s), 10.25 (1H, s), 11.70 (1H, br s); IR (solid) 1663, 1595, 1563,1509, 1422, 1331, 1240, 1176, 1053, 999; MS 417.3 (M+H)⁺

Example 110

[1127][2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)amine(IIc-31):

[1128] Prepared in a manner similar to the above described Method A toafford a white solid, mp 222° C.; ¹H NMR (DMSO) δ 0.74 (2H, m), 0.93(2H, m), 1.92 (1H, m), 3.97 (2H, s), 5.82 and 6.65 (1H, 2×br s), 7.29(3H, m), 7.50 (1H, m), 7.66 (1H, m), 7.92 (2H, m), 8.39 (1H, m), 9.21and 9.85 (1H, 2×br s), 9.90 and 10.56 (1H, 2×s), 12.19 and 12.80 (1H,2×br s); IR (solid) 1641, 1622, 1595, 1581, 1554, 1513, 1486, 1463,1408, 1372, 985, 821; MS 382.3 (M+H)⁺

Example 111

[1129][2-(Benzothiazol-6-ylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-32):

[1130] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 255-256° C.; ¹H NMR (DMSO) δ 0.73 (2H, m),0.92 (2H, m), 1.92 (1H, m), 5.83 and 6.63 (1H, 2×br s), 7.27 (1H, br s),7.59 (1H, br s), 7.68 (1H, br s), 7.79 (1H, br s), 7.98 (1H, br s), 8.41(1H, br s), 8.97 (1H, br s), 9.19 (1H, s), 9.58 and 10.10 (1H, 2×br s),10.57, 12.21 and 12.85 (1H, 3×br s); IR (solid) 1624, 1592, 1575, 1512,1472, 1411, 1377, 1333, 1244; MS 400.3 (M+H)⁺

Example 112

[1131](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylamino)-quinazolin-4-yl]-amine(IIc-33):

[1132] Prepared in a manner similar to the above described Method A toafford a white solid, mp 245-246° C.; ¹H NMR (DMSO) δ 0.72 (2H, br s),0.90 (2H, br s), 1.90 (1H, m), 2.18 (3H, s), 2.23 (3H, s), 5.77 and 6.63(1H, 2×br s), 7.09 (1H, d), 7.23 (1H, br s), 7.47 (1H, br s), 7.59 (1H,br s), 7.64 (1H, br s), 8.36 (1H, br s), 9.02, 9.55 and 10.07 (1H, 3×brs), 10.49, 12.31 and 12.80 (1H, 3×br s); IR (solid) 1620, 1600, 1574,1552, 1497, 1474, 1436, 1416, 1385, 1262; MS 371.5 (M+H)⁺

Example 113

[1133](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2-phenoxyethylamino)-quinazolin-4-yl]-amine(IIc-34):

[1134] Prepared in a manner similar to the above described Method A toafford a white solid, mp 203° C.; ¹H NMR (DMSO) >0.70 (2H, m), 0.88 (2H,m), 1.87 (1H, m), 3.73 (2H, d), 4.16 (2H, s), 5.75 and 6.70 (1H, 2×brs), 6.93 (1H, t), 6.90-7.20 (3H, m), 7.20-7.45 (3H, m), 7.55 (1H, s),7.76 (1H, br s), 8.32 (1H, s), 9.95 and 10.35 (1H, 2×s), 12.13 and 12.75(1H, 2×br s); IR (solid) 3434, 1622, 1600, 1572, 1554, 1499, 1476, 1422,1399, 1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M+H)⁺

Example 114

[1135](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(thiophen-2-methylamino)-quinazolin-4-yl]-amine(IIc-35):

[1136] Prepared in a manner similar to the above described Method A toafford a white solid, mp 212° C.; ¹H NMR (DMSO) δ 0.67 (2H, m), 0.90(2H, m), 1.86 (1H, m), 4.74 (2H, d), 5.76 and 6.66 (1H, 2×br s), 6.95(1H, s), 6.90-7.20 (2H, m), 7.20-8.45 (5H, m), 9.94 and 10.40 (1H, 2×s),12.13 and 12.71 (1H, 2×br s); IR (solid) 3444, 2948, 2847, 1622, 1600,1559, 1500, 1481, 1418, 1390, 1358, 1336, 1313, 1263, 1217, 1185, 1149,990, 821; MS 363.4 (M+H)⁺

Example 115

[1137][2-(4-Carboxymethylphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-36):

[1138] Prepared in a manner similar to the above described Method A toafford a brown solid, mp >210° C. (dec.); ¹H NMR (DMSO) δ 0.64 (2H, brs), 0.92 (2H, m), 1.92 (1H, m), 3.50 (2H, s), 5.76 and 6.54 (1H, 2×s),7.19 (1H, s), 7.24 (1H, m), 7.49 (1H, d), 7.64 (1H, t), 7.84 (2H, d),8.37 (1H, m), 10.27 and 12.25 (1H, 2×br s); IR (solid) 1648, 1591, 1555;1512, 1489, 1428, 1411, 1374; MS 401.4 (M+H)⁺

Example 116

[1139](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1H-indazol-5-ylamino)-quinazolin-4-yl]-amine(IIc-37):

[1140] Prepared in a manner similar to the above described Method A toafford a purple solid, mp 268-271° C.; ¹H NMR (DMSO) δ 0.69 (2H, br s),0.90 (2H, m), 1.88 (1H. m), 5.86 and 6.58 (1H, 2×s), 7.22 (1H, s), 7.61(1H, s), 7.71 (2H, m), 8.01 (1H, s), 8.37 (2H, s), 8.58, 9.05 and 9.58(1H, 3×br s), 10.01, 10.68 and 12.38 (1H, 3×br s), 12.90 (1H, s); IR(solid) 1626, 1605, 1576, 1546, 1512, 1495, 1476, 1447, 1431, 1416,1393, 1261, 1224; MS 383.3 (M+H)⁺

Example 117

[1141](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(pyridin-3-ylmethylamino)-quinazolin-4-yl]-amine(IIc-38):

[1142] Prepared in a manner similar to the above described Method A toafford a yellow solid, mp 193° C.; ¹H NMR (DMSO) δ 0.69 (2H, m), 0.89(2H, m), 1.86 (1H, m), 4.60 (2H, s), 5.76, 6.22 and 6.66 (1H, 3×br s),7.10 (1H, s), 7.33 (2H, s), 7.54 (1H, s), 7.78 (1H, s), 8.31 (1H, s),8.44 (1H, s), 8.61 (1H, s), 10.00 and 10.32 (1H, 2×s), 12.15 and 12.63(1H, 2×br s); IR (solid) 2927, 2850, 1623, 1600, 1577, 1536, 1477, 1418,1332, 1254, 814; MS 358.3 (M+H)⁺

Example 118

[1143](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylamino)-quinazolin-4-yl]-amine(IIc-39):

[1144] Prepared in a manner similar to the above described Method A toafford a white solid, mp 228-231° C.; ¹H NMR (DMSO) δ 0.73 (2H, br s),0.91 (2H, m) , 1.92 (1H, m), 3.88 (3H, s), 5.99 and 6.79 (1H, 2×s), 7.27(1H, s), 7.46 (3H, m), 7.68 (1H, s), 8.36 (1H, d), 8.48 (2H, s), 9.36,9.84 and 10.00 (1H, 3×br S), 10.63, 12.17 and 12.79 (1H, 3×br s); IR(solid) 1716, 1615, 1591, 1579, 1557, 1473, 1432, 1416, 1379, 1334,1298, 1276, 1226, 1191, 1142, 1110, 1020, 985; MS 401.3 (M+H)⁺

Example 119

[1145][2-(3-Carboxyphenylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-40):

[1146] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 298-302° C.; ¹H NMR (DMSO) δ 0.73 (2H, brs), 0.91 (2H, m), 1.90 (1H, m), 7.26 (1H, s), 7.35 (1H, t), 7.50 (2H,d), 7.66 (1H, t), 8.31 (2H, m), 8.41 (1H, d); IR (solid) 1661, 1597,1578, 1558, 1517, 1486, 1424, 1385; MS 387.3 (M+H)⁺

Example 120

[1147](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-ethylphenylamino)-guinazolin-4-yl]-amine(IIc-41):

[1148] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 186-188° C.; ¹H NMR (DMSO) δ 0.73 (2H, brs), 0.91 (2H, br s), 1.22 (3H, t), 1.90 (1H, m), 2.62 (2H, d), 5.81 and6.70 (1H, 2×br S), 6.78 (1H,d), 7.20 (2H, s), 7.48 (1H, s), 7.65 (1H,s), 7.69 (1H, s), 7.81 (1H, s), 8.38 (1H, br s), 9.03, 9.74 and 10.03(1H, 3×br s), 10.55, 12.16 and 12.82 (1H, 3×br s); IR (solid) 1614,1580, 1549, 1534, 1493, 1471, 1433, 1409, 1374, 1340, 1240, 1182, 1165,1138; MS 371.3 (M+H)⁺

Example 121

[1149](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dimethylphenylamino)-quinazolin-4-yl]-amine(IIc-42):

[1150] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 241-242° C.; ¹H NMR (DMSO) δ 0.58 (2H, brs), 0.86 (2H, d), 1.77 (1H, br s), 2.11 (3H, br s), 2.28 (3H, s), 5.77and 6.14 (1H, 2×br s,), 7.01 (1H, s), 7.11 (1H, t), 7.22 (1H, br s),7.29 (1H, d), 7.56 (1H, s), 8.36 (1H, br s), 8.49, 8.98 and 9.98 (1H,3×br s), 10.48, 12.04 and 12.68 (1H, 3×br s); IR (solid) 1622, 1603,1573, 1552, 1495, 1471, 1440, 1428, 1412, 1384, 1268; MS 371.4 (M+H)⁺

Example 122

[1151](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylamino)-quinazolin-4-yl]-amine(IIc-43):

[1152] Prepared in a manner similar to the above described Method A toafford a grey solid, mp 144° C.; ¹H NMR (DMSO) δ 0.69 (2H, s), 0.86 (2H,d), 1.89 (1H, m), 3.61 (3H, s), 3.67 (3H, s), 5.76 (1H, br s), 6.12 (1H,d), 6.31 (1H, s), 6.66 (1H, d), 6.94 (1H, d), 7.27 (1H, t), 7.50 (1H,d), 7.68 (1H, t), 8.45 and 9.36 (1H, br s, rotamers), 9.42 and 10.54(1H, s, rotamers), 12.29 and 12.82 (1H, br s, rotamers); IR (solid)3331, 3000, 2959, 2931, 2836, 1627, 1604, 1577, 1536, 1509, 1463, 1441,1418, 1336, 1259, 1232, 1200, 1027; MS 403.8 (M+H)⁺

Example 123

[1153](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyphenylamino)-quinazolin-4-yl]-amine(IIc-44):

[1154] Prepared in a manner similar to the above described Method A toafford a grey solid, mp 207-211° C.; ¹H NMR (DMSO) δ 0.73 (2H, br s),0.91 (2H, br s), 1.91 (1H, m), 3.77 (3H, s), 5.81 and 6.71 (1H, 2×br s),6.53 (1H, d), 7.19-7.85 (7H, m), 8.34 (1H, s), 9.08, 9.79 and 10.06 (1H,3×br s), 10.56, 12.16 and 12.82 (1H, 3×br s); IR (solid) 1611, 1580,1549, 1533, 1498, 1477, 1430, 1409, 1374, 1337, 1253, 1204, 1180, 1157,1141, 1041, 1030, 992; MS 373.7 (M+H)⁺

Example 124

[1155](5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8-tetrahydroquinazolinin-4-yl)-amine(IIc-45):

[1156] Prepared in a manner similar to the above described Method C.

Example 125

[1157][2-(Biphenyl-3-ylamino)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIc-46):

[1158] Prepared in a manner similar to the above described Method A toafford a pale brown solid, mp 153° C.; ¹H NMR (DMSO) δ 0.73 (2H, s),0.90 (2H, d), 1.89 (1H, m), 5.83 and 6.70 (1H, br s, rotamers), 7.25(2H, d), 7.32 (2H, m), 7.50 (3H, t), 7.68 (3H, m), 8.00 (1H, d), 8.22(1H, br s), 8.40 (1H, br s), 9.20 and 9.89 (1H, br s, rotamers), 10.06and 10.46 (1H, s, rotamers), 12.17 and 12.84 (1H, br s, rotamers); IR(solid) 3333, 1627, 1609, 1581, 1540, 1504, 1472, 1449, 1426, 1335,1248, 1216, 1102, 988, 819; MS 419.3 (M+H)⁺

Example 126

[1159](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-phenylprop-1-ylamino)-quinazolin-4-yl]-amine(IIc-47):

[1160] Prepared in a manner similar to the above described Method A toafford a white solid, mp 189° C.; ¹H NMR (DMSO) δ 0.71 (2H, s), 0.91(2H, s), 1.89 (3H, s), 2.69 (2H, s), 3.37 (2H, s), 5.76 and 6.66 (1H, brs, rotamers), 6.95-7.60 (8H, m), 8.10-8.40 (1H, m), 9.89 and 10.30 (1H,br s, rotamers), 12.10 and 12.75 (1H, br s, rotamers); IR (solid) 1622,1595, 1572, 1545, 1499, 1481, 1417, 1390, 1367, 1048, 997, 829; MS 385.4(M+H)⁺

Example 127

[1161][2-(4-acetamido-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-48):

[1162] Prepared in a manner similar to the above described Method-A toafford a pale brown solid, mp 251° C.; ¹H NMR (DMSO) 8 2.04 (3H, s),2.19 (3H, s), 2.56 (3H, s), 5.92 and 6.80 (1H, br s, rotamers), 7.22(2H, s), 7.48 (1H, s), 7.64 (1H, s), 7.73 (2H, s), 8.40 (1H, s), 9.05and 9.74 (1H, br s, rotamers), 9.20 (1H, s), 10.05 and 10.54 (1H, br s,rotamers), 12.15 and 12.82 (1H, br s, rotamers); IR (solid) 3309, 2972,2936, 1641, 1604, 1577, 1536, 1504, 1468, 1423, 1409, 1377, 1341, 1304,1259, 1223, 1100, 1009, 864; MS 388.2 (M+H)⁺

Example 128

[1163](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(indan-2-ylamino)-quinazolin-4-yl]-amine(IIc-49):

[1164] Prepared in a manner similar to the above described Method A toafford a brown solid, mp 233-234° C.; ¹H NMR (DMSO) δ 0.65 (2H, s), 0.84(2H, s), 1.83 (1H, s), 2.91 (2H, m), 3.33 (2H, s), 4.72 (1H, s), 6.07(1H, br s), 7.00-7.60 (8H, m), 8.29 (1H, s), 10.30 (1H, br s), 12.24(1H, br s); IR (solid) 3425, 2941, 2836, 1622, 1595, 1572, 1540, 1495,1476, 1426, 1394, 1248, 1025, 1007, 870, 833; MS 383.3 (M+H)⁺

Example 129

[1165][2-(3-Methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-50):

[1166] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 240-242° C.; ¹H NMR (DMSO) δ 2.25 (3H, s),2.30 (3H, s), 5.95 (1H, br s), 6.76 (1H, d), 7.10-7.35 (2H, m), 7.48(1H, s), 7.55-7.85 (3H, m), 8.40 (1H, s), 9.05 and 9.74 (1H, br s,rotamers), 10.07 and 10.55 (1H, br s, rotamers), 12.14 and 12.81 (1H, brs, rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549, 1536, 1481,1445, 1408, 1372, 1330, 1267, 1239, 1184, 1166, 1139, 993, 838, 806; MS331.3 (M+H)⁺

Example 130

[1167][2-(2-Chloro-5-methylphenylamino)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-51):

[1168] Prepared in a manner similar to the above described Method A toafford a grey solid, mp 246-247° C.; ¹H NMR (DMSO) δ 2.19 (3H, s), 2.31(3H, s), 6.37 (1H, br s), 6.94 (1H, d), 7.23 (1H, s), 7.37 (1H, d), 7.43(1H, d), 7.64 (1H, t), 7.97 (1H, s), 8.19 (1H, s), 8.42 (1H, br s),10.17 (1H, br s), 12.19 (1H, br s); IR (solid) 3409, 2918, 2850, 1627,1591, 1573, 1545, 1513, 1486, 1463, 1418, 1386, 1332, 1291, 1259, 1182,1000, 827; MS 365.2 (M+H)⁺

Example 131

[1169](5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(morpholin-1-yl)phenylamino]-quinazolin-4-yl}-amine(IIc-52):

[1170] Prepared in a manner similar to the above described Method A toafford a grey solid, mp 275-276° C.; ¹H NMR (DMSO) δ 0.71, (2H, s), 0.90(2H, s), 1.89 (1H, s), 3.05 (4H, s), 3.75 (4H, s), 5.78 and 6.61 (1H, brs, rotamers), 6.93 (2H, s), 7.20 (1H, s), 7.43 (1H, s), 7.50-7.90 (3H,m), 8.39 (1H, s), 8.95 and 9.58 (1H, br s, rotamers), 10.07 and 10.47(1H, br s, rotamers), 12.16 and 12.81 (1H, br s, rotamers); IR (solid)3245, 2990, 2972, 2959, 2936, 2918, 1618, 1577, 1559, 1509, 1477, 1445,1413, 1382, 1264, 1223, 1150, 1109, 1050, 923, 882, 823; MS 428.3 (M+H)⁺

Example 132

[1171][2-(Benzothiazol-6-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-53): Prepared in a manner similar to the above described Method Ato afford an off-white solid, mp 236-239° C.; ¹H NMR (DMSO) δ 2.25(3H_(,) s), 6.35 (1H, br s), 7.22 (1H, t), 7.53 (1H, d), 7.62 (1H, t),7.76 (1H, d), 7.98 (1H, d), 8.39 (1H, d), 9.05 (1H, s), 9.17 (1H, s),9.59 (1H, br s), 10.30 (1H, br s), 12.35 (1H, br s); IR (solid) 1622,1605, 1567, 1546, 1505, 1473, 1441, 1417, 1385, 1341, 1297, 1273, 1253,1192, 1130; MS 374.1 (M+H)⁺

Example 133

[1172][2-(3,4-Dimethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-54):

[1173] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 249-251° C.; ¹H NMR (DMSO) δ 2.18 (3H, brs), 2.21 (3H, br s), 2.24 (3H, br s), 5.92 and 6.80 (1H, 2×br s), 7.05(1H, br s), 7.21 (1H, br s), 7.46 (1H, br s), 7.64 (3H, br s), 8.37 (1H,br s), 9.00, 9.51 and 9.73 (1H, 3×br s), 10.12, 10.54 and 12.17 (1H,3×br s); IR (solid) 1616, 1582, 1547, 1505, 1473, 1452, 1413, 1368,1334, 1294, 1246, 1210, 1188, 1170, 1139; MS 345.3 (M+H)⁺

Example 134

[1174][2-(3-Ethylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-55):

[1175] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 238-239° C.; ¹H NMR (DMSO) δ 1.21 (3H, t),2.25 (3H, br s), 2.61 (2H, q), 5.92 and 6.80 (1H, 2×br s), 6.78 (1H, d),7.21 (2H, br s), 7.48 (1H, br s), 7.65 (1H, s), 7.72 (1H, s), 7.80 (1H,s), 8.40 (1H, br s), 9.09, 9.58 and 10.10 (1H, 3×br s), 10.54, 12.26 and12.81 (1H, 3×br s); IR (solid) 1619, 1556, 1535, 1471, 1441, 1407, 1377,1341, 1274, 1246, 1185, 1167, 1139, 995; MS 345.5 (M+H)⁺

Example 135

[1176][2-(3-Methoxyphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-56):

[1177] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 212-215° C.; ¹H NMR (DMSO) δ 2.25 (3H, brs), 3.77 (3H, s), 5.92 and 6.84 (1H, 2×br s), 6.55 (1H, d), 7.13 (2H,m), 7.41-7.50 (2H, m), 7.65 (1H, s), 7.77 (1H, s), 8.41 (1H, br s),9.10, 9.79 and 10.10 (1H, 3×br s), 10.55, 12.13 and 12.82 (1H, 3×br s);IR (solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277, 1256, 1201,1159; MS 347.4 (M+H)⁺

Example 136

[1178][2-(4-Acetamido-3-cyanophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-57):

[1179] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 294-296° C.; ¹H NMR (DMSO) δ 2.08 (3H, s),2.28 (3H, s), 6.67 (1H, br s), 7.27 (1H, s), 7.43 (1H, d), 7.53 (1H, s),7.68 (1H, s), 8.04 (1H, d), 8.45 (2H, s), 9.41, 10.35 and 12.18 (2H,3×br s), 10.00 (1H, s); IR (solid) 1620, 1583, 1558, 1237, 1508, 1477,1446, 1413, 1373, 1341, 1292, 1259, 1241, 1180, 1162, 1142, 1105, 1030,1000; MS 399.2 (M+H)⁺

Example 137

[1180][2-(2-Methoxybiphenyl-5-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-58):

[1181] Prepared in a manner similar to the above described Method A toafford a white solid, 222-223° C.; ¹H NMR (DMSO) δ 2.22 (3H, s), 3.75(3H, s), 6.82 (1H, br s), 7.05-7.11 (1H, m), 7.15-7.25 (1H, m),7.30-7.36 (1H, m), 7.40-7.50 (3H, m), 7.49-7.55 (2H, m), 7.55-7.70 (1H,m), 7.70-7.82 (1H, m), 7.90-8.02 (1H, m), 8.30-8.50 (1H, m); IR (solid)1625, 1604, 1574, 1556, 1496, 1473, 1444, 1403, 1384, 1258, 1234, 1182,1018, 824, 806, 755, 698; MS 423.4 (M+H)⁺

Example 138

[1182][2-(4-Acetamidophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-59):

[1183] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 253-256° C.; ¹H NMR (DMSO) δ 2.02 (3H, s),2.25 (3H, br s), 5.92 and 6.77 (1H, 2×br s), 7.21 (1H, s), 7.49 (3H, s),7.63 (1H, s), 7.83 (2H, d), 8.38 (1H, br s), 9.03 and 10.05 (1H, 2×brs), 9.81 (1H, s), 12.13 and 12.80 (1H, 2×br s); IR (solid) 1669, 1635,1617, 1574, 1535, 1512, 1486, 1422, 1394, 1366, 1316, 1268, 1231, 1184,1119, 1101; MS 374.1 (M+H)⁺

Example 139

[1184][2-(4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(IIc-60):

[1185] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 238-242° C.; 1H NMR (DMSO) 6 1.48 (9H, s),2.24 (3H, s), 6.23 (1H, br s), 7.12 (1H, s), 7.36 (3H, s), 7.54 (1H, s),7.67 (2H, d), 8.30 (1H, d), 9.14 (2H, br s), 10.24 and 12.19 (1H, 2×brs); IR (solid) 1698, 1620, 1555, 1520, 1475, 1443, 1405, 1371, 1310,1241, 1167, 1055, 996; MS 432.1 (M+H)⁺

Example 140

[1186][2-(4-Cyanophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-61):

[1187] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 293-298° C.; ¹H NMR (DMSO) δ 2.25 (3H, s),6.50 (1H, br s), 7.27 (1H, s), 7.51 (1H, s), 7.64 (1H, s), 7.71 (2H, d),8.40 (1H, s), 9.76 (1H, br s), 10.34 (1H, br s), 12.33 (1H, br s); IR(solid) 1633, 1605, 1571, 1517, 1505, 1469, 1418, 1337, 1255, 1174,1000; MS 342.1 (M+H)⁺

Example 141

[1188](5-Methyl-2H-pyrazol-3-yl)-[2-(6-oxo-6,10b-dihydro-4H-benzo[c]chromen-2-ylamino)-quinazolin-4-yl]-amine(IIc-62):

[1189] Prepared in a manner similar to the above described Method A toafford a pale yellow solid, mp 293-298° C.; ¹H NMR (DMSO) δ 1.72 (3H, brs), 6.23 (1H, br s), 7.50 (1H, t), 7.66 (2H, t), 7.75 (1H, t), 7.87 (1H,t), 7.77 (1H, t), 8.26 (1H, d), 8.33 (1H, d), 8.58-8.72 (2H, m), 10.55(1H, s), 11.55 (1H, s), 12.40 (1H, s); IR (solid) 1707, 1629, 1607,1579, 1540, 1497, 1488, 1471, 1446, 1428, 1417, 1346, 1332, 1298, 1270,1255, 1207, 1114, 998, 816, 793, 766, 758, 710, 685; MS 435.4 (M+H)⁺

Example 142

[1190][2-(Biphenyl-3-ylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine(IIc-63):

[1191] Prepared in a manner similar to the above described Method A toafford a pale brown solid, mp 206-207° C.; ¹H NMR (DMSO) δ 2.20 (3H,s),6.80 (1H, br s), 7.24-7.27 (2H, m), 7.36-7.40 (2H, m), 7.48-7.52 (3H,m), 7.67-7.69 (3H, m), 7.94 (1H, m), 8.26 (1H, m), 8.42 (1H, m), 9.30(1H, br s), 10.16 (1H, br s), 12.13 (1H, br s); IR (solid) 1593, 1578,1544, 1498, 1479, 1414, 1384, 1251, 1209, 1003; MS 393.2 (M+H)⁺

Example 143

[1192][2-(4-Methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-64):

[1193] Prepared in a manner similar to the above described Method A toafford a white solid, mp 245-246° C.; ¹H NMR (DMSO) δ 2.23 (3H, s), 2.26(3H, s), 3.63 (3H, s), 3.64 (2H, s), 5.99 (0.5H, br s), 6.80 (0.5 H, brs), 7.10 (1H, m), 7.25 (1H, m), 7.50 (1H, m), 7.61-7.80 (3H, m), 8.44(1H, m), 9.10 (0.5H, br s), 9.78 (0.5H, br s), 10.11 (0.5H, br s), 10.56(0.5H, br s), 12.18 (0.5H, br s), 12.90 (0.5H, br s); IR (solid) 1732,1710, 1622, 1581, 1554, 1538, 1508, 1490, 1446, 1411, 1371, 1336, 1306,1257, 1244, 1204, 1146, 1016, 998, 797, 754, 692; MS 403.4 (M+H)⁺

Example 144

[1194][2-(4-Carboxymethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine(IIc-65):

[1195] A solution of[2-(4-methoxycarbonylmethyl-3-methylphenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water (3/1, 8 mL)was treated with 1M NaOH (2 mL, 2 mmol). The mixture was heated at 70°C. for 2 hours and then neutralised with 1M HCl (2 mL, 2 mmol). Thesolid that formed was collected by filtration to afford the titlecompound (185 mg, 95%) as a pale yellow solid, mp 245° C. (dec.); ¹H NMR(DMSO) δ 2.27 (6H, 2×s), 3.55 (2H, s), 6.49 (1H, s), 7.13 (1H, d), 7.26(1H, t), 7.50 (1H, d), 7.62-7.78 (3H, m), 8.42 (1H, d), 9.34 (1H,d),10.26 (1H, s), 12.36 (1H, s); IR (solid) 1660, 1590, 1562, 1504, 1427,1385, 810, 776, 751, 693; MS 389.4 (M+H)⁺

Example 145

[1196][2-(4-Aminophenylamino)-quinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine(IIc-66):

[1197] A solution of[2-(4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-60, 100 mg, 0.232 mmol) in a mixture of DCM/TFA (5/1, 12 mL) wasstirred for 2 hours at room temperature. The solvents were removed invacuo and the residue triturated in aqueous K₂CO₃. The resulting solidwas collected by filtration and washed with diethyl ether to affordIIc-66 (69 mg, 90%) as an off-white solid, mp 164-167° C.; ¹H NMR (DMSO)δ 2.24 (3H, s), 6.33 (1H, br s), 7.12 (2H, d), 7.48 (3H, m), 7.58 (1H,d), 7.86 (1H, t), 8.64 (1H, d), 10.86 (1H, br s), 11.46 (1H, s); IR(solid) 1681, 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H)⁺

Example 146

[1198][2-(4-Bromophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine(IIc-67):

[1199] Prepared in a manner similar to the above described Method A toafford an off-white solid, mp 290-293° C.; ¹H NMR (DMSO) δ 2.27 (3H, s),6.71 (1H, br s), 7.22 (1H, m), 7.46-7.50 (3H, m), 7.66 (1H, m),7.92-7.94 (2H, m), 8.38 (1H, m), 9.28, 10.11 and 12.13 (3H, 3×br s); IR(solid) 1619, 1572, 1548, 1486, 1436, 1409, 1372, 1238, 1186, 1136,1071, 997; MS 395.1/397.1 (M+H)⁺

Example 147

[1200][2-(4-Isobutyrylamino-phenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-68):

[1201] Prepared in a manner similar to the above described Method A toafford a yellow solid, mp 176-179° C.; ¹H NMR (DMSO) δ 1.11 (6H, d),2.15 (3H, s), 2.62 (1H, m), 6.25 (1H, br s), 7.41 (1H, d), 7.46 (1H, t),7.63 (1H, d), 7.71 (2H, d), 7.84 (1H, t), 8.64 (1H, d), 10.00 (1H, s),10.34 (1H, br s), 11.47 (1H, br s), 12.47 (1H, br s); IR (solid) 1676,1653, 1585, 1561, 1512, 1423, 1407, 1312, 1199, 1177, 1128; MS 402.3(M+H)⁺

Example 148

[1202](5-Ethyl-2H-pyrazol-3-yl)-[2-(5-ethyl-2H-pyrazol-3-ylamino)-quinazolin-4-yl]-amine(IIc-69):

[1203] To a solution of 2,4-dichloroquinazoline (0.5 g, 2.51 mmol) and3-amino-5-ethylpyrazole (558 mg, 5.02 mmol) in ethanol (10 mL) was addedtriethylamine (0.35 mL, 2.51 mmol) and the resulting mixture was stirredfor 3 hours at room temperature. The resulting pale yellow precipitatewas collected by filtration, washed with cold ethanol and dried undervacuum to afford IIc-69 (306 mg, 35%) as an off-white solid, mp 248-252°C.; ¹H NMR (DMSO) δ 1.30 (m, 6H), 2.72 (m, 4H), 6.12 (br.s, 1H), 6.54and 6.90 (br. s, 1H), 7.58 (t, 1H), 7.74 (d, 1H), 7.90 (t, 1H), 8.78 (d,1H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2 (M+H)⁺

Example 149

[1204] (1H-Indazol-3-yl)-(2-phenylamino-quinazolin-4-yl)-amine (IIc-70):

[1205] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 6.90 (m, 3H), 7.11 (t, 1H), 7.19(m, 2H), 7.44 (t, 1H), 7.57 (m, 1H), 7.62 (d, 1H), 7.67 (d, 2H), 7.71(d, 1H), 7.93 (t, 1H), 8.59 (d, 1H), 11.55 (br. s, 1H), 13.15 (s, 1H);MS 353.2 (M+H)⁺

Example 150

[1206](1H-Indazol-3-yl)-[2-(3-trifluoromethylphenylamino)-quinazolin-4-yl]-amine(IIc-71):

[1207] Prepared in a manner similar to the above described Method A toafford a pale yellow solid. ¹H NMR (DMSO) δ 7.00 (t, 1H), 7.02 (d, 1H),7.22 (d, 1H), 7.37 (td, 1H), 7.56 (m, 3H), 7.61 (d, 1H), 7.66 (d, 2H),7.92 (t, 1H), 8.60 (d, 1H), 10.61 (br. s, 1H), 11.42 (br. s, 1H), 13.12(s, 1H); MS 421.2 (M+H)⁺

Example 151

[1208](1H-Indazol-3-yl)-[2-(4-trifluoromethylphenylamino)-quinazolin-4-yl]-amine(IIc-72):

[1209] Prepared in a manner similar to the above described Method A toafford a pale yellow solid. ¹H NMR (DMSO) δ 7.08 (t, 1H), 7.16 (d, 2H),7.44 (m, 3H), 7.58 (t, 1H), 7.6 (t, 2H), 7.69 (d, 1H), 7.95 (t, 1H),8.62 (d, 1H), 10.82 (br. s, 1H), 11.50 (br. s, 1H), 12.20 (s, 1H); MS421.2 (M+H)⁺

Example 152

[1210] [2-(Adamantan-2-ylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-73):

[1211] Prepared in a manner similar to the above described Method A toafford a white solid. ¹H NMR (DMSO) δ 0.83 (br. s, 1H), 0.85 (br. s,1H), 1.44 (m, 4H), 1.55 (m, 3H), 1.63 (s, 2H), 1.73 (s, 1H), 1.82 (s,1H), 1.84 (s, 1H), 3.56 (m, 1H), 7.10 (t, 1H), 7.41 (t, 1H), 7.51 (t,1H), 7.54 (d, 1H), 7.57 (d, 1H), 7.69 (d, 1H), 7.90 (t, 1H), 8.45 (d,1H), 8.58 (d, 1H), 11.60 (s, 1H), 13.10 (s, 1H); MS 411.3 (M+H)⁺

Example 153

[1212] (1H-Indazol-3-yl)-(2-methyl-phenyl-amino-quinazolin-4-yl)-amine(IIc-74):

[1213] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 3.27 (s, 1H), 6.88 (t, 1H), 6.93(t, 2H), 7.04 (t, 1H), 7.14 (d, 2H), 7.22 (t, 1H), 7.36 (m, 2H), 7.48(d, 1H), 7.54 (d, 1H), 7.62 (t, 1H), 8.37 (d, 1H), 10.11 (s, 1H), 12.71(s, 1H); MS 367.2 (M+H)⁺

Example 154

[1214][2-(2-Chloro-phenyl)-amino-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-75):

[1215] Prepared in a manner similar to the above described Method A toafford a white solid. ¹H NMR (DMSO) δ 6.81 (t, 1H), 6.87 (td, 1H), 7.07(t, 1H), 7.34 (dd, 1H), 7.35 (t, 1H), 7.40 (t, 1H), 7.53 (d, 1H), 7.56(d, 1H), 7.63 (d, 2H), 7.72 (t, 1H), 8.07 (d, 1H), 8.46 (d, 1H), 10.37(s, 1H), 12.89 (s, 1H); MS 387.1 (M+H)⁺

Example 155

[1216](1H-Indazol-3-yl)-[2-(2-trifluoromethylphenylamino)-quinazolin-4-yl]-amine(IIc-76):

[1217] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 7.01 (t, 1H), 7.20 (m, 1H), 7.32(m, 1H), 7.36 (t, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.61(t, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.95 (t, 2H), 8.62 (d, 1H), 10.15(m, 1H), 11.62 (s, 1H), 13.03 (s, 1H); MS 421.2 (M+H)⁺

Example 156

[1218][2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-77):

[1219] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 13.16 (s, 1H), 11.49 (br. s, 1H),10.38 (br. s, 1H), 8.58 (d, 1H), 7.92 (t, 1H), 7.67 (t, 2H), 7.61 (d,1H), 7.56 (m, 1H), 7.44 (t, 1H), 7.22 (m, 2H), 7.08 (t, 1H), 6.86 (m,2H), 3.87 (s, 2H); MS 392.2 (M+H)⁺

Example 157

[1220][2-(4-Chlorophenylamino)-5,6,7,8-tetrahydroquinazolinin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-78):

[1221] Prepared in a manner similar to the above described Method C; MS355.5 (M+H)⁺

Example 158

[1222](5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl)-amine(IIc-79):

[1223] Prepared in a manner similar to the above described Method C; MS335.3 (M+H)⁺

Example 159

[1224][2-(Benzimidazol-2-ylamino)-7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-80):

[1225] Prepared in a manner similar to the above described Method C; MS452.0 (M+H)⁺

Example 160

[1226](7-Benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)amine(IIc-81):

[1227] Prepared in a manner similar to the above described Method C; MS412.1 (M+H)⁺

Example 161

[1228][6-Benzyl-2-(4-chlorophenylamino)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-82):

[1229] Prepared in a manner similar to the above described Method C; MS446.3 (M+H)⁺

Example 162

[1230][2-(Benzimidazol-2-ylamino)-6-benzyl-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-83):

[1231] Prepared in a manner similar to the above described Method C; MS452.2 (M+H)⁺

Example 163

[1232](6-Benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIc-84):

[1233] Prepared in a manner similar to the above described Method C; MS411.9 (M+H)⁺

Example 164

[1234](5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-amine(IIc-85):

[1235] Prepared in a manner similar to the above described Method C; MS322.3 (M+H)⁺

Example 165

[1236][2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-amine(IIc-86):

[1237] Prepared in a manner similar to the above described Method A toafford an off-white solid; ¹H NMR (DMSO) δ 13.65 (s, 1H), 12.82 (br. s,1H), 11.69 (br. s, 1H), 8.55 (dd, 2H), 8.12 (d, 1H), 7.88 (m, 1H), 7.66(m, 1H), 7.50 (m, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 6.94 (m, 2H), 3.89(s, 2H); MS 393.1 (M+H)⁺.

Example 166

[1238][2-(4-Cyanobenzylamino)-quinazolin-4-yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-amine(IIc-87):

[1239] Prepared in a manner similar to the above described Method A toafford an off-white solid; ¹H NMR (DMSO) δ 13.68 (s, 1H), 12.82 (br. s,1H), 11.70 (br. s, 1H), 8.55 (m, 3H), 8.00 (d, 1H), 7.92 (t, 1H), 7.59(m, 4H), 6.96 (m, 2H), 6.86 (m, 1H), 4.23 (s, 2H); MS 393.1 (M+H)⁺.

Example 167

[1240][2-(4-Cyanomethylphenylamino)-quinazolin-4-yl]-(4-fluoro-1H-indazol-3-yl)-amine(IIc-88):

[1241] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 13.49 (s, 1H), 11.61 (br. s, 1H),10.64 (br. s, 1H), 8.56 (d, 1H), 7.95 (t, 1H), 7.67 (d, 1H), 7.58 (t,1H), 7.46 (t, 1H), 7.43 (dd, 1H), 7.14 (m, 2H), 6.85 (dd, 3H), 3.88 (s,2H); MS 410.1 (M+H)⁺.

Example 168

[1242] [2-(4-Cyanophenylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-89):

[1243] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 13.14 (s, 1H), 11.31 (br. s, 1H),10.51 (br. s, 1H), 8.59 (d, 1H), 7.91 (t, 1H), 7.65 (d, 3H), 7.56 (t,1H), 7.50 (m, 2H), 7.45 (dd, 1H), 7.26 (d, 2H), 7.08 (t, 1H); MS 378.2(M+H)⁺.

Example 169

[1244] [2-(4-Cyanobenzylamino)-quinazolin-4-yl]-(1H-indazol-3-yl)-amine(IIc-90):

[1245] Prepared in a manner similar to the above described Method A toafford a white solid; ¹H NMR (DMSO) δ 13.12 (s, 1H), 12.91 (br. s, 1H),11.60 (br. s, 1H), 8.57 (d, 1H), 7.91 (t, 1H), 7.63 (d, 1H), 7.55(m,5H), 7.38 (t, 1H), 6.89 (t, 1H), 6.84 (br. d, 2H), 4.19 (s, 2H); MS392.2 (M+H)⁺.

Example 170

[1246](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-yloxy)-quinazolin-4-yl]-amine(IIb-1):

[1247] Prepared in a manner similar to the above described Method B toafford a white solid, mp 327-328° C.; ¹H NMR (DMSO) δ-0.05-0.07 (2H, m),0.50-0.68 (2H, m), 1.28-1.40 (1H, m), 5.68 (1H,s), 7.40-7.50 (2H, m),7.50-7.64 (3H, m), 7.70-7.80 (2H, m), 7.82-8.08 (3H, m), 8.64 (1H,d),10.58 (1H, s), 12.07 (1H, s); IR (solid) 1621, 1595, 1575, 1554, 1508,1480, 1410, 1385, 1320, 1254, 1240, 1212, 1166, 830, 819, 758; MS 394.4(M+H)⁺

Example 171

[1248] (5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-yloxy)quinazolin-4-yl]-amine (IIb-2):

[1249] Prepared in a manner similar to the above described Method B toafford a pale brown solid, mp >300° C; ¹H NMR (DMSO) δ 1.62 (3H, s),5.65 (1H, s), 7.96 (2H, br s), 7.55 (3H, d), 7.76 (2H, m), 7.92 (1H, d),8.00 (2H, m), 8.58 (1H, d), 10.56 (1H, s), 11.99 (1H, s); IR (solid)1625, 1601, 1571, 1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159; MS368.7 (M+H)⁺

Example 172

[1250] (5-Methyl-2H-pyrazol-3-yl)-(2-phenoxy-quinazolin-4-yl)-amine(IIb-3):

[1251] Prepared in a manner similar to the above described Method B toafford a tan solid, mp 287-290° C.; ¹H NMR (DMSO) δ 2.10 (3H, s), 5.92(1H, s), 7.23 (2H, d), 7.29 (1H, t), 7.38 (1H, t), 7.46-7.53 (3H, m),7.85 (1H, t), 8.58 (1H, d), 10.55 (1H, s), 12.11 (1H, s); IR (solid)1622, 1602, 1572, 1556, 1542, 1477, 1454, 1402, 1373, 1316, 1249, 1200,1172, 1158; MS 318.3 (M+H)⁺

Example 173

[1252](II-Cyclopropyl-2H-pyrazol-3-yl)-[2-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-quinazolin-4-yl]-amine(IIb-4):

[1253] Prepared in a manner similar to the above described Method B toafford a solid, mp 277-279° C.; ¹H NMR (DMSO) δ 0.40-0.50 (2H, m),0.89-0.96 (2H, m), 1.71-1.87 (5H, m), 2.70-2.83 (4H, m), 5.88 (1H, s),6.88-6.96 (2H, m), 7.12 (1H, d), 7.39 (1H,t), 7.58 (1H, d), 7.76 (1H,t), 8.58 (1H, d), 10.54 (1H, s), 12.20 (1H, s); IR (solid) 1731, 1641,1614, 1570, 1506, 1495, 1464, 1424, 1362, 1340, 1240, 880, 831, 812,776, 758; MS 398.4 (M+H)⁺

Example 174

[1254](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenoxy)-quinazolin-4-yl]-amine(IIb-5):

[1255] Prepared in a manner similar to the above described Method B toafford an off-white solid, mp 283-284° C.; ¹H NMR (DMSO) δ 0.49-0.53(2H, m), 0.89-0.96 (2H, m), 1.72-1.81 (1H, m), 2.40 (3H, s), 5.82 (1H,s), 7.03 (1H, d), 7.08 (1H, s), 7.15 (1H, d), 7.35-7.46 (2H, m), 7.58(1H, d), 7.78 (1H, t), 8.62 (1H, d), 10.58 (1H, s), 12.25 (1H, s); IR(solid) 1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319, 1253, 1189,1158, 997, 842, 789, 763; MS 358.4 (M+H)⁺

Example 175

[1256][2-(3-Methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-6):

[1257] Prepared in a manner similar to the above described Method B toafford a white solid, mp 277-278° C.; ¹H NMR (DMSO) δ 2.15 (3H, s), 3.78(3H, s), 6.00 (1H, s), 6.77-6.90 (3H, m), 7.30-7.41 (2H, m), 7.52 (1H,d), 7.70 (1H, t), 8.59 (1H, d), 10.57 (1H, s), 12.10 (1H, s); IR (solid)1623, 1603, 1575, 1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142,1046, 1022, 833, 760; MS 348.4 (M+H)⁺

Example 176

[1258][2-(3,4-Dimethoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-7):

[1259] Prepared in a manner similar to the above described Method B toafford an off-white solid, mp 277-278° C.; ¹H NMR (DMSO) δ 2.09 (3H, s),3.70 (3H, s), 3.78 (3H, s), 5.98 (1H, s), 6.73-6.77 (1H, m), 6.90 (1H,s), 7.00 (1H, d), 7.35-7.45 (1H, m), 7.58 (1H, d), 7.70-7.78 (1H, m),8.63 (1H, d), 10.55 (1H, s), 12.19 (1H, s).; IR (solid) 1626, 1603,1576, 1557, 1509, 1481, 1436, 1409, 1382, 1372, 1318, 1249, 1227, 1195,1180, 1158, 1120, 1029, 965, 835, 803, 767, 753; MS 378.4 (M+H)⁺

Example 177

[1260][2-(Benzo[1,3]dioxol-5-yloxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-8):

[1261] Prepared in a manner similar to the above described Method B toafford an off-white solid, mp 296-299° C. (dec.); ¹H NMR (DMSO) δ 2.13(3H, s), 6.05 (1H, s), 6.09 (2H, s), 6.69 (1H, d), 6.90 (1H, s), 6.98(1H, d), 7.39 (1H, t), 7.53 (1H, d), 7.70 (1H,t), 8.58 (1H, d), 10.59(1H, s); IR (solid) 1602, 1577, 1538, 1508, 1499, 1481, 1455, 1401,1377, 1323, 1251, 1241, 1169, 1121, 1038, 1022, 951, 935, 863, 813, 752;MS 362.4 (M+H)⁺

Example 178

[1262][2-(3-Methoxycarbonylphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIb-9):

[1263] Prepared in a manner similar to the above described Method B toafford an off-white solid, mp 269-270° C.; ¹H NMR (DMSO) δ 2.05 (3H, s),3.90 (3H, s), 5.88 (1H, s), 7.00-7.90 (7H, m), 8.50-8.65 (1H, m), 10.65(1H, s); IR (solid) 1722, 1626, 1605, 1578, 1559, 1507, 1429, 1378,1317, 1282, 1272, 1255, 1204, 1185, 1096, 1021, 990, 869, 841, 758; MS362.4 (M+H)⁺

Example 179

[1264](5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine(IId-1):

[1265] Prepared in a manner similar to the above described Method C toafford a pale yellow solid, mp 265-267° C.; ¹H NMR (DMSO) δ 0.67 (2H,m), 0.93 (2H, m), 1.87 (1H, m), 5.19 (2H, s), 6.55 (1H, br s), 6.90-7.02(3H, m), 7.26-7.30 (2H, m), 7.54 (1H, m), 7.74-7.83 (2H, m), 8.61 (1H,m), 10.45 (1H, br s), 12.18 (1H, br s); MS 358.4 (M+H)⁺

Example 180

[1266](2-Benzyloxymethyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IId-2):

[1267] Prepared in a manner similar to the above described Method C toafford a white solid, mp 211-213° C.; ¹H NMR (DMSO) δ 0.65 (2H, m), 0.90(2H, m), 1.86 (1H, m), 4.63 (2H, s), 4.68 (1H, s), 6.71 (1H, s),7.28-7.54 (6H, m), 7.76-7.81 (2H, m), 8.61 (1H, m), 10.41 (1H, s), 12.19(1H, s); MS 372.3 (M+H)⁺

Example 181

[1268] (2-Benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IId-3):

[1269] Prepared in a manner similar to the above described Method D toafford a white solid, mp 219-221° C.; ¹H NMR (DMSO) δ 0.66 (2H, m), 0.95(2H, m), 1.87 (1H, m), 4.11 (2H, s), 6.31 (1H, s), 7.20-7.50 (6H, m),7.71-7.79 (2H, m), 8.55 (1H, m), 10.27 (1H, s), 12.15 (1H, s); MS 342.7(M+H)⁺

Example 182

[1270] (5-Cyclopropyl-2H-pyrazol-3-yl)-(2-methyl-quinazolin-4-yl)-amine(IId-4):

[1271] Prepared in a manner similar to the above described Method C toafford a white solid, mp 289-290° C.; ¹H NMR (DMSO) δ 2.31 (3H, s), 2.71(3H, s), 6.73 (1H, s), 7.75 (2H, q), 8.04 (1H, t), 8.82 (1H, s), 11.94(1H, s), 12.65 (1H, s); IR (solid) 3266, 1636, 1607, 1579, 1479, 1407,769, 668; MS 240.4 (M+H)⁺

Example 183

[1272][2-(4-Chlorophenoxymethyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-5):

[1273] Prepared in a manner similar to the above described Method C toafford a white solid; ¹H NMR (DMSO) δ 1.58 (2H, m), 1.68 (2H, m), 1.85(2H, m), 2.20 (3H, s), 2.90 (2H, m), 3.00 (2H, m), 5.26 (2H, s), 6.15(1H, s), 7.15 (2H, d), 7.40 (2H, d), 10.25 (1H, br); MS 384.3 (M+H)⁺.

Example 184

[1274][2-(4-Chlorophenoxymethyl)-5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-6):

[1275] Prepared in a manner similar to the above described Method C toafford a white solid; ¹H NMR (DMSO) δ 1.80 (4H, m), 2.15 (3H, s), 2.55(2H, m obscured), 2.75 (2H, m), 5.25 (2H, s), 6.12 (1H, s), 7.08 (2H,d), 7.35 (2H, d), 9.80 (1H, br); MS 370.2 (M+H)⁺.

Example 185

[1276](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-ylsulfanyl)-6-phenylpyrimidin-4-yl]-amine(IIIa-1):

[1277] Prepared in a manner similar to the above described Method L toafford a white solid, mp 233-234° C.; ¹H NMR (DMSO) δ 0.21 (2H, br s),0.56 (2H, br s), 1.17 (1H, br m), 5.35 (1H, br s), 7.02 (1H, br s), 7.49(3H, m), 7.59 (2H, m), 7.73 (1H, d), 7.88 (2H, m), 8.02 (3H, m), 8.30(1H, m), 10.01 (1H, s), 11.75 (1H, br s); IR (solid); MS 436.7(M+H)⁺

Example 186

[1278](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonyl-phenylylsulfanyl)-6-phenylpyrimidin-4-yl]-amine(IIIa-2):

[1279] Prepared in a manner similar to the above described Method L toafford a white solid, mp 126-129° C.; ¹H NMR (DMSO) δ 0.52 (2H, m), 0.87(2H, m), 1.69 (1H, m), 3.87 (3H, s), 5.47 (1H, s), 7.03 (1H, br s), 7.49(3H, m), 7.67 (1H, m), 7.87 (2H, m), 7.94 (1H, m), 8.09 (1H, m), 8.23(1H, m), 10.07 (1H, s), 11.94 (1H, s); IR (solid); MS 444.7(M+H)⁺

Example 187

[1280](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-3):

[1281] Prepared in a manner similar to the above described Method L toafford a white solid, mp 248-250° C.; ¹H NMR (DMSO) δ 0.21 (2H, br s),0.55 (2H, br s), 0.94 (1H, br m), 5.31 (1H, br s), 6.55 (1H, br s),7.57-7.66 (3H, m), 7.99-8.03 (4H, m), 8.25 (1H, s), 9.94 (1H, s), 11.75(1H, br s); IR (solid); MS 360.7(M+H)⁺

Example 188

[1282](5-Cyclopropyl-2H-pyrazol-3-yl)-[5,6-dimethyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-4):

[1283] Prepared in a manner similar to the above described Method L toafford a white solid, mp >270° C.; ¹H NMR (DMSO) δ 0.14 (2H, d), 0.45(2H, d), 0.78 (1H, s), 2.05 (3H, s), 2.27 (3H, S), 5.26 (1H, S), 7.60(3H, d), 7.99 (3H, d), 8.21 (1H, s), 8.66 (1H, s), 11.60 (1H, s); IR(solid) 1560, 1508, 1478, 1288, 1176, 1109, 994, 809, 740, 669; MS388.7(M+H)⁺

Example 189

[1284](5-Cyclopropyl-2H-pyrazol-3-yl)-[5-methyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-5):

[1285] Prepared in a manner similar to the above described Method L toafford a white solid, mp 197° C.; ¹H NMR (DMSO) δ 0.21 (2H, d), 0.51(2H, d), 0.78 (1H, s), 2.08 (3H, s), 5.40 (1H, S), 7.57 (2H, d), 7.62(1H, d), 7.92 (1H, s), 7.97 (3H, d), 8.22 (1H, s), 8.88 (1H, s), 11.70(1H, s); IR (solid) 1738, 1583, 1563, 1488, 1460, 1364, 1234, 1216, 808,656; MS 374.2(M+H)⁺

Example 190

[1286](5-Cyclopropyl-2H-pyrazol-3-yl)-[6-methyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-6):

[1287] Prepared in a manner similar to the above described Method L toafford a white solid, mp 232° C.; ¹H NMR (DMSO) δ 0.15 (2H, s), 0.51(2H, s), 0.92 (1H, s), 2.20 (3H, s), 5.22 (1H, s), 7.60 (2H, s), 7.67(1H, d), 7.98 (3H, s), 8.24 (1H, s), 9.79 (1H, s), 11.60 (1H, s); IR(solid) 1586, 1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666; MS374.2(M+H)⁺

Example 191

[1288](5-Cyclopropyl-2H-pyrazol-3-yl)-[6-(morpholin-4-yl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-7):

[1289] To a solution of 2,4,6-trichloropyrimidine (600 mg, 3.27 mmol)and 3-amino-5-cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 mL)was added triethylamine (456 μL, 3.27 mmol) and the reaction mixture wasstirred for 15 hours at room temperature. The solvent was evaporated andthe residue was purified by flash chromatography (SiO₂, Hexane/AcOEtgradient) to afford(5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (705mg, 80%).

[1290] To a solution of(5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (211mg, 0.781 mmol) and 2-naphthalenethiol (125 mg, 0.781 mmol) intert-butanol (5 mL) was added triethylamine (174 μL, 1.25 mmol) and theresulting mixture was heated at reflux for 15 hours. The reactionmixture was cooled to room temperature and partitioned between ethylacetate and aqueous NaHCO₃. The organic layer was washed with brine,dried over MgSO₄ and concentrated in vacuo. The residue was purified byflash chromatography (SiO₂, Hexane/AcOEt gradient) to afford[6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

[1291] The above formed[6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(70 mg, 1.78.10⁻⁴ mol) was dissolved in morpholine (3 mL) and themixture heated at 120° C. for 15 hours. The solvent was evaporated andthe residue was purified by flash chromatography to afford IIIa-7 (50mg, 63%) as a white solid, mp 118-120° C.; ¹H NMR (DMSO) δ 0.34-0.91(4H, 4×m), 1.28 and 1.78 (1H, 2×m), 3.32 (2H, m), 3.60 (6H, m),5.38-6.16 (2H, br m), 7.55-7.66 (3H, m), 7.95-8.02 (3H, m), 8.19 and8.23 (1H, 2×s), 9.28 and 9.31 (1H, 2×br s), 11.71 and 11.84 (1H, 2×brs); IR (solid); MS 445.2(M+H)⁺

Example 192

[1292](5-Cyclopropyl-2H-pyrazol-3-yl)-[6-(1-methylpiperazin-4-yl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-8):

[1293] Prepared in a manner substantially similar to the method describeabove for compound IIIb-7 to afford a white solid, mp 113-115° C.; ¹HNMR (DMSO) δ 0.35-0.91 (4H, 4×m), 1.31 and 1.78 (1H, 2×m), 2.17 and 2.19(3H, 2×s), 2.29 (4H, m), 3.35 (2H, m), 3.61 (2H, m), 5.38-6.20 (2H, brm), 7.55-7.66 (3H, m), 7.95-8.02 (3H, m), 8.17 and 8.23 (1H, 2×s), 9.26and 9.32 (1H, 2×br s), 11.71 and 11.85 (1H, 2×br s); IR (solid); MS458.3(M+H)⁺

Example 193

[1294][6-(2,6-Dimethylphenyl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-9):

[1295] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 148-152° C.; ¹H NMR (DMSO) δ 2.10 (6H, s),2.26 (3H, d), 5.09 and 6.31 (1H, 2×br s), 7.03 (3H, s), 7.22 (1H, s),7.59 (2H, t), 7.69 (1H, d), 7.99 (3H, d), 8.28 (1H, s), 9.93 (1H, s),11.67 (1H, br s); IR (solid) 2970, 1739, 1436, 1365, 1229, 1217, 1205;MS 438.3(M+H)⁺

Example 194

[1296][6-(2-Methylphenyl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-10):

[1297] Prepared in a manner similar to the above described Method L toafford a white solid, mp 211-214° C.; ¹H NMR (DMSO) δ 1.41 (3H, s), 2.30(3H, s), 5.26 and 6.55 (1H, 2×br s), 7.34 (5H, m), 7.62 (2H, t), 7.70(1H, d), 7.99 (3H, t), 8.30 (1H, s), 9.97 (1H, s), 11.73 (1H, br s); IR(solid) 2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0(M+H)⁺

Example 195

[1298][2-(4-Acetamido-phenylsulfanyl)—6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-11):

[1299] Prepared in a manner similar to the above described Method L toafford a white solid, mp 153-155° C.; ¹H NMR (DMSO) δ 2.01 (3H, s), 2.08(3H, s), 5.43 (1H, s), 6.96 (1H, br s), 7.49-7.88 (9H, m), 10.00 (1H, brs), 10.23 (1H, s), 11.86 (1H, br s); MS 417.2(M+H)⁺

Example 196

[1300](5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-6-phenyl-pyrimidin-4-yl]-amine(IIIa-12):

[1301] Prepared in a manner similar to the above described Method L toafford a white solid, mp 237-239° C.; ¹H NMR (DMSO) δ 1.39 (3H, br s),5.12 (1H, br s), 6.98 (1H, br s), 7.50 (3H, m), 7.62-7.63 (2H, m), 7.72(1H, d), 7.90 (2H, m), 8.03-8.05 (3H, m), 8.31 (1H, s), 10.00 (1H, s),11.73 (1H, br s); IR (solid) ; MS 410.2(M+H)⁺

Example 197

[1302][2-(4-Isobutyrylylamino-phenylsulfanyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-13):

[1303] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 201-202° C.; ¹H NMR (DMSO) δ 1.05-1.13(6H, m), 1.97 (3H, s), 2.65 (1H, m), 5.37 (1H, br s), 6.93 (1H, br s),7.50-7.58 (5H, m), 7.78-7.90 (4H_(,) m), 9.99, 10.12 and 11.84 (3H, 3×br s); IR (solid) 1676, 1614, 1586, 1573, 1514, 1483, 1395, 1299, 1262,1242, 1214, 1168, 1089, 988; MS 445.3 (M+H)⁺

Example 198

[1304][6-(4-Methylpiperazin-1-yl)-2-methylsulfanyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-14):

[1305] Prepared in a manner similar to the above described Method M toafford an off-white solid; ¹H NMR (DMSO) 67 2.18 (3H, s), 2.20 (3H, s),2.36 (4H, m), 2.41 (3H, s), 3.46 (4H, m), 5.91 (1H, s), 6.41 (1H, br s),9.20 (1H, S), 11.87 (1H, s); IR (solid); MS 320.3(M+H)⁺

Example 199

[1306](5-Methyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionylamino-phenylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-15):

[1307] Prepared in a manner similar to the above described Method L toafford a pale pink solid, mp 204-206° C.; ¹H NMR (DMSO) δ 1.09-1.13 (3H,m), 2.00 (3H, s), 2.33-2.37 (2H, m), 5.40 (1H, br s), 6.95 (1H, br s),7.50 (3H, m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.88 (2H, m), 9.99,10.15 and 11.85 (3H, 3×br s); IR (solid) 1678, 1623, 1580, 1534, 1496,1453, 1398, 1307, 1245, 1203, 1119, 1049, 1030, 1004; MS 431.2(M+H)⁺

Example 200

[1308][2-(4-Cyclopropanecarbonylamino-phenylsulfanyl)-6-phenylpyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-16):

[1309] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 253-255° C.; ¹H NMR (DMSO) δ 0.82-0.83(4H, m), 1.83 (1H, m), 2.00 (3H, s), 5.41 (1H, br s), 6.88 (1H, br s),7.42-7.50 (3H, m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.89 (2H, m),9.99, 10.47 and 11.85 (3H, 3×br s); IR (solid) 1672, 1621, 1591, 1581,1573, 1537, 1495, 1448, 1405, 1390, 1312, 1254, 1246, 1202, 1192, 1179,1119.2, 1005, 959; MS 443.2(M+H)⁺

Example 201

[1310](5-Methyl-2H-pyrazol-3-yl)-{6-phenyl-2-[4-(propane-1-sulfonylamino)-phenylsulfanyl]-pyrimidin-4-yl}-amine(IIIa-17):

[1311] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 232-235° C.; ¹H NMR (DMSO) δ 0.94 (3H, t),1.71 (2H, m), 2.12 (3H,s), 3.13 (2H, t), 5.59 (1H, s), 7.31 (2H, d),7.49 (3H, s), 7.59 (2H, d), 7.85 (2H, s), 10.00 (1H, br s), 10.16 (1H,s), 12.05 (1H, br s); IR (solid) 1628, 1587, 1545, 1525, 1496, 1455,1311, 1255, 1236, 1212, 1186, 1140, 1032, 1001, 934; MS 481.2(M+H)⁺

Example 202

[1312][2-(4-Ethanesulfonylamino-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-18):

[1313] Prepared in a manner similar to the above described Method L toafford a pale yellow solid, mp 251-254° C.; ¹H NMR (DMSO) δ 1.21 (3H,t), 2.12 (3H,s), 3.15 (2H, q), 5.59 (1H, s), 7.32 (2H, d), 7.49 (3H, s),7.57 (2H, d), 7.85 (2H, s), 9.99 (1H, br s), 10.15 (1H, br s), 11.90(1H, br s); IR (solid) 1621, 1585, 1542, 1523, 1495, 1455, 1315, 1257,1208, 1142, 1049, 1033, 1002, 932; MS 467.2(M+H)⁺

Example 203

[1314][2-(4-Acetamidophenyl-sulfanyl)-6-(2-methylphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-19):

[1315] Prepared in a manner similar to the above described Method L toafford a white solid, mp 212-214° C.; ¹H NMR (DMSO) δ 2.01 (3H, s), 2.08(3H, s), 2.24 (3H, s), 5.43 (1H, s), 6.56 (1H, br s), 7.49-7.88 (9H, m),10.00 (1H, br s), 10.23 (1H, s), 11.86 (1H, br s); IR (solid1701, 1634,1588, 1555, 1496, 1390, 1307, 1208, 1169, 823, 803; MS 431.4(M+H)⁺

Example 204

[1316][2-(4-Isobutanecarbonylamino-phenyl-sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-20):

[1317] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 241-243° C.; ¹H NMR (DMSO) δ 0.95-0.96(6H, m), 2.00 (3H, s), 2.11 (1H, m), 2.23-2.25 (2H, m), 5.43 (1H, br s),6.95 (1H, br s), 7.50-7.58 (5H, m), 7.77-7.89 (4H, m), 10.00, 10.13 and11.84 (3H, 3×br s); IR (solid) 1660, 1628, 1589, 1575, 1543, 1525, 1496,1451, 1398, 1357, 1314, 1301, 1251, 1206, 1108, 995; MS 459.2 (M+H)⁺

Example 205

[1318][2-(4-Acetamido-phenyl-sulfanyl)-5-methyl-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-21):

[1319] Prepared in a manner similar to the above described Method L toafford a pale pink solid, mp 276-277° C.; ¹H NMR (DMSO) δ 1.98 (3H, s),2.08 (6H, s), 5.41 (1H, br s), 7.47-7.55 (7H, m), 7.72-7.74 (2H, m),8.89, 10.20 and 11.87 (3H, 3×br s); IR (solid) 1676, 1591, 1555, 1540,1519, 1493, 1393, 1375, 1303, 1260, 1230, 1176, 1148, 1045, 1011, 969;MS 431.2 (M+H)⁺

Example 206

[1320][2-(4-Acetamido-phenyl-sulfanyl)-6-(4-ethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-22):

[1321] Prepared in a manner similar to the above described Method L toafford an off white solid, mp 241-245° C.; ¹H NMR (DMSO) δ 1.99 (3H,s),2.06 (3H, s), 3.82 (3H, s), 5.44 (1H, s), 7.03 (2H, d), 7.53 (2H, d),7.71 (2H, s), 7.83 (2H, s), 10.12 (1H, s), 10.23 (1H, s), 11.84 (1H, s);IR (solid) 1627, 1606, 1571, 1511, 1313, 1257, 1181, 830; MS 447.2(M+H)⁺

Example 207

[1322][6-(3-Acetamidophenyl)-2-(4-acetamido-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-23):

[1323] Prepared in a manner similar to the above described Method L toafford a brown solid, mp 227-230° C.; ¹H NMR (DMSO) δ 2.01 (3H, s), 2.11(6H, s), 5.34 (1H, s), 6.99 (1H, br s), 7.41 (1H, t), 7.49-7.62 (3H, m),3.71-3.76 (3H, m), 8.19 (1H s), 10.09-10.18 (2H, br s), 10.23 (1H, s),12.20 (1H, br s); IR (solid) 1635, 1573, 1533, 1488, 1372, 1318, 1297,827, 798; MS 474.3 (M+H)⁺

Example 208

[1324][2-(4-Isopropanesulfonylamino-phenyl-sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-24):

[1325] Prepared in a manner similar to the above described Method L toafford a white solid, mp 255-257° C.; ¹H NMR (DMSO) δ 1.28 (6H, d), 2.14(3H,s), 3.32 (1H, s), 5.60 (1H, s), 7.36 (2H, d), 7.49 (3H, s), 7.60(2H, d), 7.85 (2H, s), 10.00 (1H, br s), 10.11 (1H, s), 11.92 (1H, brs); IR (solid) 1625, 1587, 1574, 1545, 1525, 1495, 1313, 1295, 1257,1234, 1136, 1000, 934; MS 481.2 (M+H)⁺

Example 209

[1326]{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-6-phenyl-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-25):

[1327] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 213-215° C.; ¹H NMR (DMSO) δ 2.00 (3H, s),2.31 (6H, s), 3.15 (2H, s), 5.45 (1H, s), 6.83 (1H, br s), 7.46-7.51(3H, m), 7.59 (2H, d), 7.80-7.92 (5H, m), 9.98 (1H, s), 10.05 (1H, s);IR (solid) 1701, 1617, 1587, 1571, 1509, 1480, 1456, 1304, 1284, 1254,1238, 1213, 1181, 1156, 987, 833, 782, 754, 695; MS 460.3(M+H)⁺

Example 210

[1328][2-(3-Chloro-benzylsulfanyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-26):

[1329] Prepared in a manner similar to the above described Method M toafford a white solid, mp 224-225° C.; ¹H NMR (DMSO) δ 2.17 (3H, s),3.40-3.50 (4H, m), 3.60-3.71 (4H, m), 4.30 (2H, s), 5.95 (1H, brs), 6.41(1H, brs), 7.23-7.55 (4H, m), 9.31 (1H, s), 11.89 (1H, brs); IR (solid)1557, 1476, 1442, 1401, 1314, 1232, 1121, 1018; MS 417.4 (M+H)⁺

Example 211

[1330][2-(3-Chloro-benzylsulfanyl)-6-(2-methoxy-ethylamino)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-27):

[1331] Prepared in a manner similar to the above described Method M toafford a white solid, mp 101-102° C.; ¹H NMR (DMSO) δ 2.15 (3H, s), 3.21(3H, s), 3.28-3.41 (4H, m), 4.29 (2H, s), 5.78 (1H, brs), 6.20 (1H,brs), 7.10 (1H, brs), 7.21-7.50 (4H, m), 9.01 (1H, brs); IR (solid)1598, 1555, 1527, 1336, 1293, 1117, 1079, 974, 783; MS 405.4 (M+H)⁺

Example 212

[1332][2-Benzylsulfanyl-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-28):

[1333] Prepared in a manner similar to the above described Method M toafford a yellow gum; ¹H NMR (CDCl₃) δ 2.23 (3H, s), 2.28 (3H, s),2.31-2.64 (4H, m), 3.30-3.65 (4H, m), 4.38 (2H, s), 5.83 (1H, s), 6.23(1H, br s), 7.17-7.49 (5H, m), 7.98-8.18 (1H, m); IR (solid) 1555, 1494,1371, 1315, 1286, 1233, 999, 977, 801, 774, 709; MS 396.4 (M+H)⁺

Example 213

[1334][2-Benzylsulfanyl-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-29):

[1335] Prepared in a manner similar to the above described Method M toafford an off-white foam; ¹H NMR (CDCl₃) δ 2.31 (3H, s), 3.39-3.80 (8H,m), 4.39 (2H, s), 5.84 (1H, s), 6.25 (1H, brs), 7.20-7.50 (5H, m), 8.10(1H, s); IR (solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767, 698;MS 383.4 (M+H)⁺

Example 214

[1336] [2-(3-Chloro-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-30):

[1337] Prepared in a manner similar to the above described Method M toafford a white foam; ¹H NMR (CDCl₃) 8 2.31 (3H, s), 2.35 (3H, s),2.40-2.51 (4H, m), 3.56-3.69 (4H, m), 4.34 (2H, s), 5.85 (1H, s), 6.29(1H, brs), 6.89 (1H, s), 7.18-7.50 (4H, m); IR (solid) 1553, 1514, 1484,1446, 1277, 1228, 999, 799; MS 430.4 (M+H)⁺

Example 215

[1338] [2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-31):

[1339] Prepared in a manner similar to the above described Method M toafford a yellow oil; ¹H NMR (CDCl₃) δ 2.28 (3H, s), 2.33 (3H, s),2.44-2.45 (4H, m), 3.62 (4H, m), 3.80 (3H, s), 4.34 (2H, s), 5.32 (1H,s), 6.28 (1H, br s), 6.83-6.85 (2 H, m), 7.34-7.36 (2H, m); IR (solid)1659, 1554, 1508, 1485, 1449, 1366, 1318, 1302, 1277, 1230, 1166, 1146,1030, 999, 973, 948; MS 443.4 (M+H)⁺

Example 216

[1340][2-(4-Acetamido-phenyl-sulfanyl)-6-tert-butyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-32):

[1341] Prepared in a manner similar to the above described Method L toafford a white solid, mp 227-228° C.; ¹H NMR (DMSO) δ 1.10 (3H, br s),1.20 (9H, s), 2.00 (3H, s), 2.35 (2H, q), 5.35 (1H, br s), 6.55 (1H, brs), 7.55 (2H, d), 7.75 (2H, d), 10.1 (1H, br s), 1.15 (1H, s), 12.1 (1H,br s); IR (solid); MS (M+H)⁺

Example 217

[1342](5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-amine(IIIa-33):

[1343] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 208-209° C.; ¹H NMR (DMSO) δ 0.52 (2H, m),0.80 (2H, m), 1.08-1.10 (3H, m), 1.65 (1H, br s), 2.33-2.37 (2H, m),5.50 (1H, br s), 7.03 (1H, br s), 7.47 (3H, m), 7.50-7.58 (2H, m),7.76-7.77 (2H, m), 7.88-7.98 (2H, m), 10.00, 10.11 and 11.86 (3H, 3×brs); IR (solid) 1676, 1617, 1575, 1539, 1520, 1485, 1459, 1418, 1395,1304, 1255, 1243, 1215, 1161, 1071, 990; MS 457.4 (M+H)⁺

Example 218

[1344][2-(3-Chloro-benzylsulfanyl)-6-(piperidin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-34):

[1345] Prepared in a manner similar to the above described Method M toafford a white solid, mp 234-235° C.; ¹H NMR (DMSO) δ 1.40-1.64 (6H, m),2.13 (3H, s), 3.42-3.51 (4H, m), 4.27 (2H, s), 5.85 (1H, br s), 6.46(1H, brs), 7.23-7.41 (3H, m), 7.48 (1H, s), 9.18 (1H, s), 11.83 (1H, s);IR (solid) 1598, 1546, 1483, 1398, 1317, 1227, 974, 798, 779; MS 415.4(M+H)⁺

Example 219

[1346](5-Methyl-2H-pyrazol-3-yl)-{2-[4-(morpholinesulfonyl)-benzylsulfanyl]-6-morpholin-4-yl-pyrimidin-4-yl}-amine(IIIa-35): Prepared in a manner similar to the above described Method Mto afford a white solid; ¹H NMR (DMSO) δ 2.24 (3H, s), 2.90-3.01 (4H,m), 3.29-3.36 (4H, m), 3.48-3.57 (4H, m), 3.67-3.75 (4H, m), 4.43 (2H,s), 5.82-6.10 (2H, m), 7.50-7.70 (5H, m); IR (solid) 1550, 1483, 1441,1346, 1308, 1255, 1160, 1112, 941, 726; MS 532.5 (M+H)⁺

Example 220

[1347]{6-(2-Methoxy-ethylamino)-2-[4-(morpholinesulfonyl)-benzylsulfanyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-36):

[1348] Prepared in a manner similar to the above described Method M toafford a white solid, mp 193-195° C.; ¹H NMR (DMSO) δ 2.15 (3H, s),2.79-2.89 (4H, m), 3.34 (3H, s), 3.40-3.51 (4H, m), 3.59-3.67 (4H, m),4.41 (2H, s), 5.76-5.72 (1H, m), 6.20 (1H, brs), 7.10 (1H, brs),7.61-7.74 (4H, m), 9.03 (1H, brs), 11.81 (1H, brs); IR (solid) 1593,1555, 1484, 1350, 1298, 1255, 1160, 1107, 936; MS 520.5 (M+H)⁺

Example 221

[1349]{6-(4-methylpiperazin-1-yl)-2-[4-(morpholinesulfonyl)-benzylsulfanyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-37):

[1350] Prepared in a manner similar to the above described Method M toafford a white solid, mp 206-207° C.; ¹H NMR (DMSO) δ 2.09 (3H, s), 2.20(3H, s), 2.26-2.40 (4H, m), 2.78-2.88 (4H, m), 3.38-3.49 (4H, m),3.56-3.67 (4H, m), 4.41 (2H, s), 5.82 (1H, brs), 6.42 (1H, brs),7.60-7.74 (4H, m), 9.26 (1H, s), 11.89 (1H, brs); IR (solid) 1583, 1558,1479, 1346, 1231, 1160, 1112, 998, 969, 926; MS 545.5 (M+H)⁺

Example 222

[1351][6-Methoxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-38):

[1352] Prepared in a manner similar to the above described Method L toafford a white solid; ¹H NMR (DMSO) δ 1.03-1.14 (3H, m), 2.00 (3H, s) ,2.29-2.40 (2H, m), OMe under DMSO, 4.22 (2H, m), 5.26 (1H, brs), 6.45(1H, brs), 7.44-7.56 (2H, m), 7.68-7.80 (2H, m), 9.86 (1H, brs), 10.11(1H, s), 11.79 (1H, brs); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360,1269, 1174, 1107; MS 399.4 (M+H)⁺

Example 223

[1353][2-(4-Methoxycarbonyl-phenyl-sulfanyl)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-39):

[1354] Prepared in a manner similar to the above described Method L toafford a white solid, mp 204-205° C.; ¹H NMR (DMSO) δ 1.89 (3H, brs),3.85 (3H, s) , OMe under DMSO, 4.23 (2H, s), 5.22 (1H, brs), 6.51 (1H,brs), 7.70-7.81 (2H, m), 7.96-8.06 (2H, m), 9.99 (1H, brs), 11.85 (1H,brs); IR (solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119,1109, 997, 841; MS 386.3 (M+H)⁺

Example 224

[1355][2-(3,5-Dimethoxy-benzylsulfanyl)-6-morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-40):

[1356] Prepared in a manner similar to the above described Method M toafford a white solid; ¹H NMR (DMSO) δ 2.15 (3H, s) , 3.40-3.49 (4H, m),3.60-3.74 (10H, m), 4.25 (2H, s), 5.88 (1H, brs), 6.31-6.61 (5H, m),9.32 (1H, s), 11.86 (1H, s); IR (solid) 1581, 1556, 1470, 1439, 1315,1232, 1205, 1159, 1144; MS 443.4 (M+H)⁺

Example 225

[1357][2-(3,5-Dimethoxy-benzylsulfanyl)-6-pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-41):

[1358] Prepared in a manner similar to the above described Method M toafford a white solid; ¹H NMR (DMSO) δ 1.80-1.97 (4H, m), 2.15 (3H, s),3.43-3.45 (4H, m), 3.69 (6H, s), 4.26 (2H, s), 5.85 (1H, brs), 6.18 (1H,brs), 6.35 (1H, brs), 6.60 (2H, s), 9.12 (1H, s), 11.88 (1H, s); IR(solid1598, 1560, 1474, 1470, 1346, 1303, 1207, 1136, 1050; MS 427.4(M+H)⁺

Example 226

[1359](5-Methyl-2H-pyrazol-3-yl)-[6-morpholin-4-yl-2-(naphthalene-2-ylmethylsulfanyl)-pyrimidin-4-yl]-amine(IIIa-42):

[1360] Prepared in a manner similar to the above described Method M toafford an off-white solid; ¹H NMR (DMSO) δ 2.15 (3H, s), 3.37-3.50 (4H,m), 3.59-3.70 (4H, m), 4.48 (2H, s), 5.88 (1H, brs), 6.40 (1H, brs),7.40-7.60 (3H, m), 7.78-7.95 (4H, m), 9.30 (1H, s), 11.89 (1H, brs); IR(solid) 1607, 1555, 1484, 1441, 1398, 1365, 1308, 1231, 1179, 1112; MS433.4 (M+H)⁺

Example 227

[1361]{2-(4-Acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-43):

[1362] Prepared in a manner similar to the above described Method N toafford a white solid, mp 219-222° C.; ¹H NMR (CDCl₃) 6.1.97-2.07 (2H,m), 2.14 (3H, s), 2.18 (3H, s), 2.30 (6H, s), 2.52 (2H, t), 4.09 (2H,t), 5.56 (1H, s), 6.80 (1H, br s), 6.99 (2H, d), 7.60 (2H, d), 7.68-7.78(3H, m), 7.85 (2H, d); IR (solid) 1606, 1590, 1512, 1482, 1309, 1250,1238, 1210, 1178, 1151, 1055, 989, 824, 711, 690, 665, 656; MS 518.4(M+H)⁺

Example 228

[1363][2-(4-Acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-44):

[1364] Prepared in a manner similar to the above described Method P toafford a white solid; MS 426.4 (M+H)⁺

Example 229

[1365][6-Hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-45):

[1366] Prepared from IIIa-48 according to Method O to afford a whitesolid; ¹H NMR (DMSO) δ 1.08-1.18 (3H, m), 1.96 (3H, brs), 2.29-2.40 (2H,m), 4.20-4.40 (3H, m), 5.20-5.46 (2H, m), 6.56 (1H, s), 7.50 (2H, d),7.79 (2H, d), 9.90 (1H, brs), 10.13 (1H, s), 11.78 (1H, brs); MS 385.4(M+H)⁺

Example 230

[1367][2-(4-Acetamido-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-46):

[1368] Prepared in a manner similar to the above described Method L toafford an off-white solid, mp 249-250° C.; ¹H NMR (DMSO) δ 1.99 (3H, s),2.08 (3H, s), 5.38 (1H, br s), 6.45 (1H, br s), 7.50 (2H, d), 7.71 (2H,d), 7.98 (1H, d), 9.89 (1H, br s), 10.19 (1H, br s), 11.83 (1H, br s);IR (solid) 1657, 1609, 1584, 1515, 1494, 1468, 1395, 1372, 1355, 1330,1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M+H)⁺

Example 231

[1369][6-(1-Butoxycarbonyl)-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-47):

[1370] Prepared in a manner similar to the above described Method L toafford a yellow solid, ¹H NMR (DMSO) δ 0.90-0.98 (3H, m), 1.03-1.12 (3H,m), 1.31-1.45 (2H, m), 1.60-1.71 (2H, m), 1.94 (3H, brs), 2.29-2.40 (2H,m), 4.20-4.30 (2H, m), 5.25 (1H, brs), 7.08 (1H, brs), 7.49-7.55 (2H,m), 7.72-7.81 (2H, m), 10.15 (1H, brs), 10.32 (1H, brs), 11.89 (1H,brs); IR (solid) 1736, 1679, 1622, 1584, 1517, 1489, 1284, 1174; MS455.4 (M+H)⁺

Example 232

[1371][6-Methoxycarbonyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIa-48):

[1372] Prepared in a manner similar to the above described Method L toafford a yellow solid; ¹H NMR (DMSO) δ 1.10 (3H, t), 1.94 (3H, brs),2.35 (2H, q), 3.84 (3H, s), 5.22 (1H, brs), 7.05 (1H, s), 7.52 (2H, d),7.79 (2H, d), 10.18 (1H, brs), 10.38 (1H, brs), 11.89 (1H, brs).; IR(solid) 1741, 1679, 1617, 1589, 1512, 1484, 1374, 1284, 1250; MS 413.4(M+H)⁺

Example 233

[1373](5-Methyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine(IIIc-1):

[1374] white solid; MS 343.4 (M+H)⁺

Example 234

[1375](5-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine(IIIc-2):

[1376] white solid, mp 267-269° C.; ¹H NMR (DMSO) δ 0.63 (2H, m), 0.96(2H, m), 1.87 (1H,m), 6.07 (1H, s), 6.84 (1H, br s), 7.20 (1H, m),7.33-8.05 (9H, m), 10.52 (1H, br s), 11.08 (1H, br s), 12.53 (1H, br s);IR (solid); MS 369.7 (M+H)⁺

Example 235

[1377](5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylamino)-6-phenyl-pyrimidin-4-yl]-amine(IIIc-3):

[1378] white solid, mp 267-270° C.; ¹H NMR (DMSO) δ 0.63 (2H, m), 0.94(2H, m), 1.87 (1H,m), 2.36 (3H, s), 6.12 (1H, s), 6.81 (1H, br s), 7.03(1H, m), 7.29-7.94 (8H, m), 10.43 (1H, br s), 11.12 (1H, br s), 12.47(1H, br s); IR (solid); MS 383.7 (M+H)⁺

Example 236

[1379][2-(4-cyanomethylphenylamino)-6-phenyl-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine(IIIc-4):

[1380] pale yellow solid, mp 294-297° C.; ¹H NMR (DMSO) δ 0.64 (2H, m),0.97 (2H, m), 1.89 (1H, m), 4.06 (2H, s), 6.07 (1H, s), 6.87 (1H, br s),7.40 (2H, m), 7.63-7.90 (5H, m), 7.95 (2H, m), 10.51 (1H, br s), 11.02(1H, br s), 12.57 (1H, br s); IR (solid); MS 408.8 (M+H)⁺

Example 237

[1381](5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(pyridin-3-ylmethylamino)-pyrimidin-4-yl]-amine(IIIc-5):

[1382] off-white solid, mp 191-193° C.; ¹H NMR (DMSO) δ 0.65 (2H, m),0.89 (2H, m), 1.83 (1H, m), 4.59 (2H, s), 6.04 (1H, br s), 6.76 (1H, brs), 7.32-7.56 (5H, m), 7.77 (1H, m), 7.88-7.97 (2H, m), 8.43 (1H, m),8.61 (1H, s), 9.47 (1H, br s), 11.93 (1H, br s); IR (solid); MS 384.8(M+H)⁺

Example 238

[1383][2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-6):

[1384] off-white solid; ¹H NMR (CD₃OD) δ 5.95 (1H, s), 6.65 (1H, s),6.90 (1H, d), 7.18 (1H, t), 7.32 (1H, d), 7.58 (1H, t), 7.82 (1H, s),8.18 (1H, d), 8.25 (1H, d), 8.65 (1H, s) ; MS 422.1 (M+H)⁺

Example 239

[1385][2-(3-Chlorophenyl)amino-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-7):

[1386] white solid; MS 467.7 (M+H)⁺

Example 240

[1387](5-Methyl-2H-pyrazol-3-yl)-[2-(4-sulfamoylphenylamino)-6-(3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-amine(IIIc-8):

[1388] white solid; MS 512.6 (M+H)⁺

Example 241

[1389][2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIIc-9):

[1390] white solid; MS 367.1 (M+H)⁺

Example 242

[1391][2-(Benzimidazol-2-ylamino-)6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-10):

[1392] MS 335.5 (M+H)⁺

Example 243

[1393][2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIIc-11):

[1394] MS 377.5 (M+H)⁺

Example 244

[1395][2-(4-Chlorophenyl)amino-6-ethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-12):

[1396] MS 329.4 (M+H)⁺

Example 245

[1397](5-tert-Butyl-2H-pyrazol-3-yl)-[2-(3-chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-amine(IIIc-13):

[1398] off-white solid; ¹H NMR (CD₃OD) δ 1.32 (9H, s), 6.18 (1H, s),7.04 (1H, s), 7.14 (1H, d), 7.35 (1H, t), 7.58 (1H, d), 7.82 (1H, t),7.91 (1H, s), 8.35 (1H, d), 8.40 (1H, d), 8.90 (1H, s); MS 464.2 (M+H)⁺

Example 246

[1399][2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIIc-14):

[1400] δ off-white solid; ¹H NMR (CD₃OD) 6 6.66 (1H, s), 7.12 (1H, d),7.30-7.45 (5H, m), 7.50 (1H, d), 7.62 (2H, d), 7.78 (1H, t), 7.88 (1H,s), 8.35 (1H, d), 8.42 (1H, d), 8.85 (1H, s); MS 484.1 (M+H)⁺

Example 247

[1401][5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-phenyl-2-phenylamino-pyrimidin-4-yl)-amine(IIIc-15):

[1402] MS 395.4 (M+H)⁺

Example 248

[1403][2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIIc-16):

[1404] MS 383.2 (M+H)⁺

Example 249

[1405][2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-[5-(Furan-2-yl)-2H-pyrazol-3-yl]-amine(IIIc-17):

[1406] MS 373.4 (M+H)⁺

Example 250

[1407][2-(4-Chlorophenylamino)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-18):

[1408] MS 315.4 (M+H)⁺

Example 251

[1409][2-(4-Chlorophenyl)amino-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-19):

[1410] MS 329.4 (M+H)⁺

Example 252

[1411](5,6-Dimethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-20):

[1412] MS 295.5 (M+H)⁺

Example 253

[1413][2-(4-Chlorophenyl)amino-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-21):

[1414] MS 345.1 (M+H)⁺

Example 254

[1415][2-(Benzimidazol-2-ylamino)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-22):

[1416] MS 351.2 (M+H)⁺

Example 255

[1417](6-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-23):

[1418] MS 311.2 (M+H)⁺

Example 256

[1419](6-Methyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIIc-24):

[1420] MS 281.1 (M+H)⁺

Example 257

[1421][2-(2-Chlorophenoxymethyl)—6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-1):

[1422] MS 392.1 (M+H)⁺

Example 258

[1423][2-(2-Chlorophenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIId-2):

[1424] MS 382.1 (M+H)⁺

Example 259

[1425](6-methyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-3):

[1426] MS 358.2 (M+H)⁺

Example 260

[1427][5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-methyl-2-phenoxymethyl-pyrimidin-4-yl)-amine(IIId-4):

[1428] MS 348.2 (M+H)⁺

Example 261

[1429][5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-methyl-2-phenylsulfanylmethyl-pyrimidin-4-yl)-amine(IIId-5):

[1430] MS 364.1 (M+H)⁺

Example 262

[1431][6-Methyl-2-(4-methyl-phenylsulfanylmethyl)-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-6):

[1432] MS 388.1 (M+H)⁺

Example 263

[1433][5-(Furan-2-yl)-2H-pyrazol-3-yl]-[6-Methyl-2-(4-methyl-phenylsulfanylmethyl)-pyrimidin-4-yl]-amine(IIId-7):

[1434] MS 378.1 (M+H)⁺

Example 264

[1435][2-(4-Fluoro-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)amine(IIId-8):

[1436] MS 376.2 (M+H)⁺

Example 265

[1437][2-(4-Fluoro-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIId-9):

[1438] MS 366.2 (M+H)⁺

Example 266

[1439](6-Ethyl-2-phenylsulfanylmethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-10):

[1440] MS 326.2 (M+H)⁺

Example 267

[1441](6-Ethyl-2-phenoxymethyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-11):

[1442] MS 310.2 (M+H)⁺

Example 268

[1443][6-Ethyl-2-(4-fluorophenoxymethyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-12):

[1444] MS 328.2 (M+H)⁺

Example 269

[1445][6-Ethyl-2-(1-methyl-1-phenyl-ethyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-13):

[1446] MS 322.2 (M+H)⁺

Example 270

[1447][2-(4-Chlororophenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine(IIId-14):

[1448] MS 392.2 (M+H)⁺

Example 271

[1449][2-(4-Chlororophenoxymethyl)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-15):

[1450] MS 330.2 (M+H)⁺

Example 272

[1451][2-(4-Chlororophenoxymethyl)-6-methoxymethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-16):

[1452] white solid; ¹H NMR (DMSO) δ 2.20 (3H, s), 3.43 (3H, s), 4.49(2H, s), 5.20 (2H, s), 6.05 (1H, br), 7.05 (2H, d), 7.33 (2H, d), 10.55(1H, br); MS 360.2 (M+H)⁺

Example 273

[1453][2-(4-Chlororophenoxymethyl)-6-methyl-pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]-amine(IIId-17):

[1454] MS 382.2 (M+H)⁺

Example 274

[1455](5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanylmethyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-amine(IId-7):

[1456] MS 352.5 (M+H)⁺

Example 275

[1457][2-(4-Methylphenylsulfanylmethyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-8):

[1458] MS 380.2 (M+H)⁺

Example 276

[1459][2-(1-Methyl-1-phenyl-ethyl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-9):

[1460] MS 362.3 (M+H)⁺

Example 277

[1461][2-(2,6-Dichlorobenzyl)-5,6,7,8-tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-10):

[1462] MS 388.1 (M+H)⁺

Example 278

[1463][7-Benzyl-2-(2,6-dichlorobenzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-11):

[1464] MS 479.5 (M+H)⁺

Example 279

[1465][6-Benzyl-2-(4-chlorophenoxymethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-12):

[1466] MS 461.2 (M+H)⁺

Example 280

[1467][2-(4-Chlorophenoxymethyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IId-13):

[1468] MS 371.3 (M+H)⁺

Example 281

[1469][2-(2,6-Dichlorobenzyl)-6-methyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-18):

[1470] MS 348.1 (M+H)⁺

Example 282

[1471][2-(2,6-Dichlorobenzyl)-5,6-dimethyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine(IIId-19):

[1472] white solid; ¹H NMR (DMSO) δ 8.50 (1H, s), 7.70 (1H, d), 7.3-7.1(3H, m), 5.25 (1H, s), 4.10 (1H, s), 2.30 (3H, s), 2.10 (3H, s), 1.80(3H, s); MS 362.1 (M+H)⁺

Example 283

[1473](1H-Indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-16):

[1474]¹HNMR (DMSO) 13.2(1H, s), 12.0(1H, s), 8.76(1H, m), 8.10(1H, m),7.85(2H, m), 7.75(1H, m), 7.61(1H, m) 7.41(1H, m), 7.30(2H, m), 7.20(2H,m), 7.12(2H, m), 2.35(2H, m), 1.60(1H, m), 1.35(1H, m); MS: m/z, 378.1MH+; HPLC R_(t)=3.21 min.

Example 284

[1475](7-Fluoro-1H-indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-17):

[1476]¹HNMR (DMSO) 13.8(1H, s), 12.05(1H, s), 8.75(1H, m), 8.10(1H, m),7.85(2H, m), 7.60(1H, m), 7.35(3H, m) 7.25-7.10(4H, m), 2.35(2H, m),1.60(1H, m), 1.35(1H, m); MS: m/z, 396.1 MH+; HPLC R_(t)=3.26 min.

Example 285

[1477](5-Fluoro-1H-indazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-18):

[1478]¹HNMR (DMSO) 13.3(1H, s), 12.0(1H, s), 8.75(1H, m), 8.10(1H, m),7.85(2H, m), 7.65(2H, m), 7.35(3H, m) 7.20(1H, m), 7.10(2H, m) 2.40 (2H,m), 1.65(1H, m), 1.35(1H, m); MS: m/z, 396.1 MH+; HPLC R_(t)=3.26 min.

Example 286

[1479](5-Methyl-1H-pyrazol-3-yl)-[2-(2-phenyl-cyclopropyl)-quinazolin-4-yl]-amine(IId-19):

[1480]¹HNMR (DMSO) 12.8 (1H, s), 11.90(1H, s), 8.80(1H, m), 8.10(1H, m),7.85(2H, m), 7.30-7.20(5H, m), 6.55 (1H, s) 2.80 (1H, m), 2.55(1H, m),2.35 (3H,s) 2.00(2H, m); MS: m/z, 342.1 MH+; HPLC R_(t)=3.13 min.

BIOLOGICAL TESTING

[1481] The activity of the compounds as protein kinase inhibitors may beassayed in vitro, in vivo or in a cell line. In vitro assays includeassays that determine inhibition of either the phosphorylation activityor ATPase activity of the activated protein kinase. Alternate in vitroassays quantitate the ability of the inhibitor to bind to the proteinkinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/protein kinasecomplex and determining the amount of radiolabel bound. Alternatively,inhibitor binding may be determined by running a competition experimentwhere new inhibitors are incubated with the protein kinase bound toknown radioligands.

Biological Testing Example 1 K_(i) Determiniation for the Inhibition ofGSK-3

[1482] Compounds were screened for their ability to inhibit GSK-3β (AA1-420) activity using a standard coupled enzyme system (Fox et al.(1998) Protein Sci. 7, 2249). Reactions were carried out in a solutioncontaining 100 mM HEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 300 μM NADH,1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were20 μM ATP (Sigma Chemicals, St Louis, Mo.) and 300 μM peptide(HSSPHQS(PO₃H₂)EDEEE, American Peptide, Sunnyvale, Calif.). Reactionswere carried out at 30° C. and 20 nM GSK-3β. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[1483] An assay stock buffer solution was prepared containing all of thereagents listed above with the exception of ATP and the test compound ofinterest. The assay stock buffer solution (175 μl) was incubated in a 96well plate with 5 μl of the test compound of interest at finalconcentrations spanning 0.002 pM to 30 pM at 30° C. for 10 min.Typically, a 12 point titration was conducted by preparing serialdilutions (from 10 mM compound stocks) with DMSO of the test compoundsin daughter plates. The reaction was initiated by the addition of 20 μlof ATP (final concentration 20 μM). Rates of reaction were obtainedusing a Molecular Devices Spectramax plate reader (Sunnyvale, Calif.)over 10 min at 30° C. The Kivalues were determined from the rate data asa function of inhibitor concentration.

[1484] The following compounds were shown to have K_(i) values less than0.1 μM for GSK-3: IIa-2, IIa-3, IIa-8, IIa-9, IIa-11, IIa-12, IIa-17,IIa-18, IIa-21 to IIa-24, IIa-26, IIa-28, IIa-30 through IIa-32, IIa-39,IIa-43, IIa-46, IIa-47, IIa-61, IIc-3, IIc-6, IIc-8, IIc-10 throughIIc-12, IIc-15, IIc-18, IIc-20 through IIc-22, IIc-24, IIc-25, IIc-27,IIc-30 through IIc-32, IIc-35 to IIc-39, IIc-42, IIc-53, IIc-61, IIc-67,IIc-77, IIc-78, IIb-1, IIb-3, IIb-5, IIb-8, IId-1, IIIa-2, IIIa-3,IIIa-6, IIIa-17, IIIa-18, IIIa-24, IIIa-27, IIIc-2 through IIIc-5,IIIc-9, IIIc-11, IIIc-12, IIIc-15, IIIc-18, IIIc-19 , IIIc-21, IIIc-24,IIIb-1 through IIIb-6, IIIb-8 through IIIb-10, IIIb-13, IIIb-14,IIId-20, IIId-21, IId-14, and IId-19.

[1485] The following compounds were shown to have K_(i) values between0.1 and 1.0 μM for GSK-3: IIa-1, IIa-4, IIa-5, IIa-7, IIa-14, IIa-15,IIa-20, IIa-29, IIa-34 through IIa-36, IIa-38, IIa-41, IIa-42, IIa-48,IIa-54, IIa-55, IIa-62, IIa-63, IIa-66, IIa-69, IIa-78, IIc-1, IIc-2,IIc-4, IIc-5, IIc-7, IIc-9, IIc-13, IIc-14, IIc-16, IIc-17, IIc-19,IIc-23, IIc-26, IIc-28, IIc-29, IIc-33, IIc-34, IIc-40, IIc-41, IIc-43through IIc-45, IIc-47 through IIc-52, IIc-54 through IIc-57, IIc-59,IIc-63 through IIc-66, IIc-72, IIc-75, IIc-76, IIc-79, IIc-6, IIb-7,IIb-9, IId-2, IId-5, IId-6, IIIa-l, IIIa-4, IIIa-5, IIIa-7, IIIa-8,IIIa-10, IIIa-11, IIIa-19, IIIa-22, IIIa-23, IIIa-26, IIIa-29, IIIa-30,IIIa-31, IIIa-33, IIIa-34, IIIa-37, IIIa-42, IIIc-l, IIIc-8, IIIc-20,IIIc-23, IIIb-7, IIIb-11, IIIb-12, IIIb-15, IIIb-16, IId-16, IId-17, andIId-18.

[1486] The following compounds were shown to have K_(i) values between1.0 and 7.0 μM for GSK-3: IIa-10, IIa-13, IIa-25, IIa-40, IIa-45,IIa-49, IIa-50 through IIa-52, IIa-64, IIa-65, IIa-67, IIa-68, IIa-71,IIa-72, IIa-74, IIa-76, IIa-77, IIa-81, IIc-58, IIc-60, IIc-62, IIc-68through IIc-71, IIc-74, IId-3, IId-4, IIIa-15, IIIa-16, IIIa-21,IIIa-28, IIIa-35, IIIa-36, IIIa-38, IIIa-41, IIIa-43, IIIa-45, IIIa-49,IIIc-lo, III-16, IIIc-17, and IIIc-22.

Biological Testing Example 2 K_(i) Determination for the Inhibition ofAurora-2

[1487] Compounds were screened in the following manner for their abilityto inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al(1998) Protein Sci 7, 2249).

[1488] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and800 μM peptide (LRRASLG, American Peptide, Sunnyvale, Calif.) was addeda DMSO solution of a compound of the present invention to a finalconcentration of 30 μM. The resulting mixture was incubated at 30 ° C.for 10 min. The reaction was initiated by the addition of 10 μL ofAurora-2 stock solution to give a final concentration of 70 nM in theassay. The rates of reaction were obtained by monitoring absorbance at340 nm over a 5 minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The K_(i) values were determined fromthe rate data as a function of inhibitor concentration.

[1489] The following compounds were shown to have K_(i) values less than0.1 μM for Aurora-2: IIa-1 through IIa-18, IIa-21 through IIa-64,IIa-66, IIa-68, IIa-69, IIa-71 through IIa-78, IIa-81, IIc-1 throughIIc-13, IIc-15 through IIc-44, IIc-46 through IIc-61, IIc-63 throughIIc-65, IIc-67 through IIc-69, IIb-1 through IIb-9, IId-1 through IId-3,IIIa-1 through IIIa-8, IIIa-10 through IIIa-13, IIIa-15 through IIIa-32,IIIa-36 through IIIa-41, IIIa-44 through IIIa-49, IIIc-1 through IIIc-5,IIIc-12, and IIIc-15.

[1490] The following compounds were shown to have K_(i) values between0.1 and 1.0 μM for Aurora-2: IIa-20, IIa-65, IIa-67, IIa-70, IIa-80,IIc-14, IIc-66, IId-5, IId-6, IIIa-14, IIIa-33 through IIIa-35, IIIc-9,IIIc-11, IIIb-1, IIIb-2, IIIb-7, IIIb-10 through IIIb-13, IIIb-15,IIIb-16, and IIId-20.

[1491] The following compounds were shown to have K_(i) values between1.0 and 10.0 μM for Aurora-2: IIa-10, IIc-71, IIc-75, IIc-76, IId-4,IIIa-42, IIIa-43, IIIc-10, IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.

Biological Testing Example 3 CDK-2 Inhibition Assay

[1492] Compounds were screened in the following manner for their abilityto inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998)Protein Sci 7, 2249).

[1493] To an assay stock buffer solution containing 0.1M HEPES 7.5, 10mM MgCl₂, 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH,30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP,and 100 μM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale,Calif.) was added a DMSO solution of a compound of the present inventionto a final concentration of 30 μM. The resulting mixture was incubatedat 30° C. for 10 min.

[1494] The reaction was initiated by the addition of 10 μL ofCDK-2/Cyclin A stock solution to give a final concentration of 25 nM inthe assay. The rates of reaction were obtained by monitoring absorbanceat 340 nm over a 5-minute read time at 30° C. using a BioRad Ultramarkplate reader (Hercules, Calif.). The K_(i) values were determined fromthe rate data as a function of inhibitor concentration.

[1495] The following compounds were shown to have K_(i) values less than1 μM for CDK-2: IIa-14, IIa-36, IIc-15, IIc-25, IIc-27, IIc-32, IIc-53,and IIIc-4.

[1496] The following compounds were shown to have K_(i) values between1.0 and 20.0 μM for CDK-2: IIa-38, IIa-40, IIa-44, IIa-52, and IIa-54.

Biological Testing Example 4 ERK Inhibition Assay

[1497] Compounds were assayed for the inhibition of ERK2 by aspectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7,2249). In this assay, a fixed concentration of activated ERK2 (10 nM)was incubated with various concentrations of the compound in DMSO (2.5%) for 10 min. at 30° C. in 0.1 M HEPES buffer, pH 7.5, containing 10 mMMgCl₂, 2.5 mM phosphoenolpyruvate, 200 μM NADH, 150 μg/mL pyruvatekinase, 50 μg/mL lactate dehydrogenase, and 200 μM erktide peptide. Thereaction was initiated by the addition of 65 μM ATP. The rate ofdecrease of absorbance at 340 nM was monitored. The IC₅₀ was evaluatedfrom the rate data as a function of inhibitor concentration.

[1498] The following compounds were shown to have K_(i) values less than1 μM for ERK-2: IIc-15, IIc-27, IIc-32, IIc-53, and IIIc-4.

[1499] The following compounds were shown to have K_(i) values between1.0 and 20.0 μM for ERK-2: IIc-18, IIc-25, and IIa-36.

Biological Testing Example 5 AKT Inhibition Assay

[1500] Compounds were screened for their ability to inhibit AKT using astandard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7,2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mMMgCl2, 25 mM NaCl , 1 mM DTT and 1.5% DMSO. Final substrateconcentrations in the assay were 170 μM ATP (Sigma Chemicals) and 200 μMpeptide (RPRAATF, American Peptide, Sunnyvale, Calif.). Assays werecarried out at 30 ° C. and 45 nM AKT. Final concentrations of thecomponents of the coupled enzyme system were 2.5 mM phosphoenolpyruvate,300 μM NADH, 30 μg/ML pyruvate kinase and 10 μg/ml lactatedehydrogenase.

[1501] An assay stock buffer solution was prepared containing all of thereagents listed above, with the exception of AKT, DTT, and the testcompound of interest. 56 μl of the stock solution was placed in a 384well plate followed by addition of 1 μl of 2 mM DMSO stock containingthe test compound (final compound concentration 30 μM). The plate waspreincubated for about 10 minutes at 30° C. and the reaction initiatedby addition of 10 μl of enzyme (final concentration 45 nM) and 1 mM DTT.Rates of reaction were obtained using a BioRad Ultramark plate reader(Hercules, Calif.) over a 5 minute read time at 30° C. Compounds showinggreater than 50% inhibition versus standard wells containing the assaymixture and DMSO without test compound were titrated to determine IC₅₀values.

[1502] The following compounds were shown to have K_(i) values between1.0 and 20.0 μM for AKT-3: IIc-18, IIc-22, IIc-25, IIc-27, IIc-31,IIc-32, IIc-37, IIc-39, IIc-42, and IIc-53.

Biological Testing Example 6 SRC Inhibition Assay

[1503] The compounds were evaluated as inhibitors of human Src kinaseusing either a radioactivity-based assay or spectrophotometric assay.

[1504] Src Inhibition Assay A: Radioactivity-based Assay

[1505] The compounds were assayed as inhibitors of full lengthrecombinant human Src kinase (from Upstate Biotechnology, cat. no.14-117) expressed and purified from baculo viral cells. Src kinaseactivity was monitored by following the incorporation of ³³p from ATPinto the tyrosine of a random poly Glu-Tyr polymer substrate ofcomposition, Glu:Tyr=4:1 (Sigma, cat. no. P-0275). The following werethe final concentrations of the assay components: 0.05 M HEPES, pH 7.6,10 mM MgCl₂, 2 mM DTT, 0.25 mg/ml BSA, 10 μM ATP (1-2 μCi ³³P-ATP perreaction), 5 mg/ml poly Glu—Tyr, and 1-2 units of recombinant human Srckinase. In a typical assay, all the reaction components with theexception of ATP were pre-mixed and aliquoted into assay plate wells.Inhibitors dissolved in DMSO were added to the wells to give a finalDMSO concentration of 2.5%. The assay plate was incubated at 30° C. for10 min before initiating the reaction with ³³P-ATP. After 20 min ofreaction, the reactions were quenched with 150 μl of 10% trichloroaceticacid (TCA) containing 20 mM Na₃PO₄. The quenched samples were thentransferred to a 96-well filter plate (Whatman, UNI-Filter GF/F GlassFiber Filter, cat no. 7700-3310) installed on a filter plate vacuummanifold. Filter plates were washed four times with 10% TCA containing20 mM Na₃PO₄ and then 4 times with methanol. 200 μl of scintillationfluid was then added to each well. The plates were sealed and the amountof radioactivity associated with the filters was quantified on aTopCount scintillation counter. The radioactivity incorporated wasplotted as a function of the inhibitor concentration. The data wasfitted to a competitive inhibition kinetics model to get the K_(i) forthe compound.

[1506] Src Inhibition Assay B: Spectrophotometric Assay

[1507] The ADP produced from ATP by the human recombinant Srckinase-catalyzed phosphorylation of poly Glu—Tyr substrate wasquanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci7, 2249). In this assay one molecule of NADH is oxidised to NAD forevery molecule of ADP produced in the kinase reaction. The disappearanceof NADH can be conveniently followed at 340 nm.

[1508] The following were the final concentrations of the assaycomponents: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/mlpoly Glu—Tyr, and 25 nM of recombinant human Src kinase. Finalconcentrations of the components of the coupled enzyme system were 2.5mM phosphoenolpyruvate, 200 μM NADH, 30 μg/ml pyruvate kinase and 10μg/ml lactate dehydrogenase.

[1509] In a typical assay, all the reaction components with theexception of ATP were pre-mixed and aliquoted into assay plate wells.Inhibitors dissolved in DMSO were added to the wells to give a finalDMSO concentration of 2.5%. The assay plate was incubated at 30° C. for10 min before initiating the reaction with 100 μM ATP. The absorbancechange at 340 nm with time, the rate of the reaction, was monitored on amolecular devices plate reader. The data of rate as a function of theinhibitor concentration was fitted to competitive inhibition kineticsmodel to get the K_(i) for the compound.

[1510] The following compounds were shown to have a K_(i) value of <100nM on SRC: IIa-8, IIa-21, IIa-23, IIa-24, IIa-27, IIa-28, IIa-30 throughIIa-33, IIb-1, IIb-4, IIb-5, IIc-3, IIc-8, IIc-10, IIc-13, IIc-15,IIc-18, IIc-19, IIc-21 through IIc-24, IIc-31 through IIc-35, IIc-37through IIc-39, IIc-41 through IIc-44, IIc-51, IId-1, IId-2, IIIa-1,IIIa-6 through IIIa-8, IIIa-26 through IIIa-30, and IIIc-1 throughIIIc-5.

[1511] The following compounds were shown to have a K_(i) value ofbetween 100 nM and 1 μM for SRC: IIa-1, IIa-2, IIa-7, IIa-9, IIa-12,IIa-14, IIa-22, IIa-25, IIa-26, IIa-29, IIa-34 through IIa-42, IIa-46,IIa-47, IIa-49 through IIa-52, IIa-56, IIa-57, IIa-59, IIa-61, IIa-62,IIa-66, IIa-67, IIa-69, IIa-72, IIa-73, IIa-75, IIb-6, IIb-8, IIc-4through IIc-7, IIc-9, IIc-11, IIc-12, IIc-14, IIc-16, IIc-17, IIc-20,IIc-25 through IIc-30, IIc-36, IIc-40, IIc-46 through IIc-50, IIc-52through IIc-61, IIc-63 through IIc-65, IIc-67, IIc-69, IId-3, IIIa-2through IIIa-5, IIIa-11, IIIa-14 through IIIa-18, IIIa-22 throughIIIa-24, IIIa-31, IIIa-33, IIIa-35, IIIa-38 through IIIa-43, andIIIa-47.

[1512] The following compounds were shown to have a K_(i) value ofbetween 1 μM and 6 μM for SRC: IIa-13, IIa-20, IIa-44, IIa-45, IIa-48,IIa-54, IIa-55, IIa-63, IIa-65, IIa-68, IIa-70, IIa-71, IIa-74, IIa-77,IIa-78, IIa-81, IIb-3, IIb-9, IIc-1, IIc-2, IIc-66, IIc-68, IIIa-13,IIIa-21, IIIa-25, IIIa-34, IIIa-36, IIIa-37, and IIIa-44.

[1513] While we have presented a number of embodiments of thisinvention, it is apparent that our basic construction can be altered toprovide other embodiments which utilize the compounds and methods ofthis invention. Therefore, it will be appreciated that the scope of thisinvention is to be defined by the appended claims rather than by thespecific embodiments which have been represented by way of example.

We claim:
 1. A compound of formula IIa:

or a pharmaceutically acceptable derivative or prodrug thereof, wherein;R^(x) and R^(y) are taken together with their intervening atoms to forma fused, unsaturated or partially unsaturated, 5-7 membered ring having0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, whereineach substitutable ring carbon of said fused ring formed by R^(x) andR^(y) is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴; R¹ is T-(Ring D); Ring D is a 5-7membered monocyclic ring or 8-10 membered bicyclic ring selected fromaryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl orheterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen,oxygen or sulfur, wherein each substitutable ring carbon of Ring D isindependently substituted by oxo, T—R⁵, or V—Z—R⁵, and eachsubstitutable ring nitrogen of Ring D is independently substituted by—R⁴; T is a valence bond or a C₁₋₄ alkylidene chain; Z is a C₁₋₄alkylidene chain; L is —O—, —S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—,—N(R⁶)—, —CO—, —CO₂—, —N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R ⁶)CON(R⁶)—,—N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—, —C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—C(R⁶)₂N(R⁶)C(O)—, —C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—,—C(R⁶)₂N(R⁶)N(R⁶)—, —C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; R2and R2′ are independently selected from —R, —T—W—R⁶, or R2 and R^(2′)are taken together with their intervening atoms to form a fused, 5-8membered, unsaturated or partially unsaturated, ring having 0-3 ringheteroatoms selected from nitrogen, oxygen, or sulfur, wherein eachsubstitutable ring carbon of said fused ring formed by R² and R^(2′) isindependently substituted by halo, oxo, —CN, —NO₂, —R⁷, or —V—R⁶, andeach substitutable ring nitrogen of said ring formed by R² and R^(2′) isindependently substituted by R⁴; R³ is selected from —R, —halo, —OR,—C(═O)R, —CO₂R, —COCOR, —COCH₂COR, —NO₂, —CN, —S(O)R, —S(O)₂R, —SR,—N(R⁴)₂, —CON(R⁷)₂, —SO₂N(R⁷)₂, —OC(═O)R, —N(R⁷)COR, —N(R⁷)CO₂(C₁₋₆aliphatic) , —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR, —N(R⁷)CON(R⁷)₂,—N(R⁷)S0₂N(R⁷)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁷)₂; each R is independentlyselected from hydrogen or an optionally substituted group selected fromC₁₋₆ aliphatic, C₆₋₁₀ aryl, a heteroaryl ring having 5-10 ring atoms, ora heterocyclyl ring having 5-10 ring atoms; each R⁴ is independentlyselected from —R⁷, —COR⁷, —CO₂ (optionally substituted C₁₋₆ aliphatic) ,—CON(R⁷)₂, or —SO₂R⁷; each R⁵ is independently selected from —R, halo,—OR, —C(═O)R, —CO₂R, —COCOR, —NO₂, —CN, —S(O)R, —SO₂R, —SR, —N(R⁴)₂,—CON(R⁴)₂, —SO₂N(R⁴)₂, —OC(═O)R, —N(R⁴)COR, —N(R⁴)CO₂ (optionallysubstituted C₁₋₆ aliphatic), —N(R⁴)N(R⁴)₂, —C═NN(R⁴)₂, —C═N—OR,—N(R⁴)CON(R⁴)₂, —N(R⁴)SO₂N(R⁴)₂, —N(R⁴)SO₂R, or —OC(═O)N(R⁴)₂; V is —O—,—S—, —SO—, —SO₂—, —N(R⁶)SO₂—, —SO₂N(R⁶)—, —N(R⁶)—, —CO—, —CO₂—,—N(R⁶)CO—, —N(R⁶)C(O)O—, —N(R⁶)CON(R⁶)—, —N(R⁶)SO₂N(R⁶)—, —N(R⁶)N(R⁶)—,—C(O)N(R⁶)—, —OC(O)N(R⁶)—, —C(R⁶)₂O—, —C(R⁶)₂S—, —C(R⁶)₂SO—,—C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—, —C(R⁶)₂N(R⁶)C(O)—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C(R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N(R⁶)—, or —C(R⁶)₂N(R⁶)CON(R⁶)—; W is —C(R⁶)₂O—,—C(R⁶)₂S—, —C(R⁶)₂SO—, —C(R⁶)₂SO₂—, —C(R⁶)₂SO₂N(R⁶)—, —C(R⁶)₂N(R⁶)—,—CO—, —CO₂—, —C(R⁶)OC(O)—, —C(R) OC(O)N(R⁶)—, —C(R⁶)₂N(R⁶)CO—,—C(R⁶)₂N(R⁶)C(O)O—, —C(R⁶)═NN(R⁶)—, —C (R⁶)═N—O—, —C(R⁶)₂N(R⁶)N(R⁶)—,—C(R⁶)₂N(R⁶)SO₂N (R)—, —C(R6)₂N(R⁶)CON(R⁶)—, or —CON(R⁶)—; each R⁶ isindependently selected from hydrogen or an optionally substituted C₁₋₄aliphatic group, or two R⁶ groups on the same nitrogen atom are takentogether with the nitrogen atom to form a 5-6 membered heterocyclyl orheteroaryl ring; and each R⁷ is independently selected from hydrogen oran optionally substituted C1-6 aliphatic group, or two R⁷ on the samenitrogen are taken together with the nitrogen to form a 5-8 memberedheterocyclyl or heteroaryl ring.
 2. The compound according to claim 1,wherein said compound as one or more features selected from the groupconsisting of: (a) R^(x) and R^(y) are taken together with theirintervening atoms to form a fused, unsaturated or partially unsaturated,5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur,or nitrogen, wherein each substitutable ring carbon of said fused ringformed by R^(x) and R^(y) is independently substituted by oxo, T—R³, orL—Z—R³, and each substitutable ring nitrogen of said ring formed byR^(x) and R^(y) is independently substituted by R⁴; (b) R¹ is T-(RingD), wherein T is a valence bond or a methylene unit; (c) Ring D is a 5-7membered monocyclic ring or an 8-10 membered bicyclic ring selected froman aryl or heteroaryl ring; (d) R² is —R or —T—W—R⁶ and R^(2′) ishydrogen; or R² and R^(2′) are taken together to form an optionallysubstituted benzo ring; and (e) R³ is selected from —R, —halo, —OR, or—N(R⁴)₂.
 3. The compound according to claim 2, wherein: (a) R^(x) andR^(y) are taken together with their intervening atoms to form a fused,unsaturated or partially unsaturated, 5-6 membered ring having 0-2heteroatoms selected from oxygen, sulfur, or nitrogen, wherein eachsubstitutable ring carbon of said fused ring formed by R^(x) and R^(y)is independently substituted by oxo, T—R³, or L—Z—R³, and eachsubstitutable ring nitrogen of said ring formed by R^(x) and R^(y) isindependently substituted by R⁴; (b) R¹ is T-(Ring D), wherein T is avalence bond or a methylene unit; (c) Ring D is a 5-7 memberedmonocyclic ring or an 8-10 membered bicyclic ring selected from an arylor heteroaryl ring; (d) R² is —R or —T—W—R⁶ and R^(2′) is hydrogen; orR² and R^(2′) are taken together to form an optionally substituted benzoring; and (e) R³ is selected from —R, —halo, —OR, or —N(R⁴)₂.
 4. Thecompound according to claim 2, wherein said compound has one or morefeatures selected from the group consisting of: (a) R^(x) and R^(y) aretaken together to form a benzo, pyrido, cyclopento, cyclohexo,cyclohepto, thieno, piperidino, or imidazo ring; (b) R¹ is T-(Ring D),wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ringor an 8-10 membered bicyclic ring selected from an aryl or heteroarylring; (c) R² is —R and R^(2′) is hydrogen, wherein R is selected fromhydrogen, C₁₋₆ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a5-6 membered heterocyclic ring; and (d) R³ is selected from —R, —halo,—OR, or —N(R⁴)₂, wherein R is selected from hydrogen,C_(1-6 l aliphatic, or) 5-6 membered heterocyclyl, phenyl, or 5-6membered heteroaryl, and L is —O—, —S—, or —N(R⁴)—.
 5. The compoundaccording to claim 4, wherein: (a) R^(x) and R^(y) are taken together toform a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno,piperidino, or imidazo ring; (b) R¹ is T-(Ring D), wherein T is avalence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10membered bicyclic ring selected from an aryl or heteroaryl ring; (c) R2is —R and R^(2′) is hydrogen, wherein R is selected from hydrogen, C₁₋₆aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 memberedheterocyclic ring; and (d) R³ is selected from —R, —halo, —OR, or—N(R⁴)₂, wherein R is selected from hydrogen, C₁₋₆ aliphatic, or 5-6membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is —O—,—S—, or —N(R⁴)—.
 6. The compound according to claim 4, wherein saidcompound has one or more features selected from the group consisting of:(a) R^(x) and R^(y) are taken together to form a benzo, pyrido,piperidino, or cyclohexo ring; (b) R¹ is T—Ring D, wherein T is avalence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; (c)R² is hydrogen or C₁₋₄ aliphatic and R^(2′) is hydrogen; (d) R³ isselected from —R, —OR, or —N(R⁴)₂, wherein R is selected from hydrogen,C₁₋₆ aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 memberedheteroaryl, and L is —O—, —S—, or —NH—; and (e) Ring D is substituted byup to three substituents selected from —halo, —CN, —NO₂, —N(R⁴)₂,optionally substituted C₁₋₆ aliphatic group, —OR, —C(O)R, —CO₂R,—CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂,wherein R is selected from hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
 7. Thecompound according to claim 6, wherein: (a) R^(x) and R^(y) are takentogether to form a benzo, pyrido, piperidino, or cyclohexo ring; (b) R¹is T—Ring D, wherein T is a valence bond and Ring D is a 5-6 memberedaryl or heteroaryl ring; (c) R² is hydrogen or C₁₋₄ aliphatic and R^(2′)is hydrogen; (d) R³ is selected from —R, —OR, or —N(R⁴)₂, wherein R isselected from hydrogen, C₁₋₆ aliphatic, 5-6 membered heterocyclyl,phenyl, or 5-6 membered heteroaryl, and L is —O—, —S—, or —NH—; and (e)Ring D is substituted by up to three substituents selected from —halo,—CN, —NO₂, —N(R⁴)₂, optionally substituted C₁₋₆ aliphatic group, —OR,—C(O)R, —CO₂R, —CONH(R⁴), —N(R⁴)COR, —N(R⁴)CO₂R, —SO₂N(R⁴)₂, —N(R⁴)SO₂R,—N(R⁶)COCH₂N(R⁴)₂, —N(R⁶)COCH₂CH₂N(R⁴)₂, or —N(R⁶)COCH₂CH₂CH₂N(R⁴)₂,wherein R is selected from hydrogen, C₁₋₆ aliphatic, phenyl, a 5-6membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
 8. Acompound selected from the group consisting of:(5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine;[2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[2,4-Bis(trifluoromethyl)phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,3-Dichlorophenylsulfanyl)—quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(l-Methylimidazol-2-ylsulfanyl)—quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Hydroxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,4-Difluorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3,4-Dimethoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3-Methylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2,6-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(2-Aminophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methylphenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxyphenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethoxyphenylsulfanyl)-quinazolin-4-yl]-amine;[2-(3-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-ylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,4-difluorophenylsulfanyl)-quinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-dichlorophenylsulfanyl)-quinazolin-4-yl]-amine;[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-dimethylphenylsulfanyl)-quinazolin-4-yl]-amine;[2-(Benzimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-1-ylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-Acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Methanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine;[2-(4-Acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(3-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Isopropanesulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Isobutyrylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-[2-(4-propionylamino-phenylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-cyclopropanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-8-hydroxyquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(propane-1-sulfonylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;[2-(4-Ethylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Isobutanecarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-7-aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;(5-Cycloprpyl-2H-pyrazol-3-yl)-[2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-amine;[2-(4-Amino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(2H-pyrazol-3-yl)-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(4-morpholin-4-yl-butyrylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-amine;[8-Methoxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(2-Dimethylamino-ethylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2Hpyrazol-3-yl)-amine;[8-Hydroxy-2-(4-methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(3-Dimethylamino-propylcarbamoyl)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)amine;{2-[4-(3-Dimethylamino-propionylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamido-phenylsulfanyl)-8-methoxy-quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-7-(3-dimethylamino-propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;(2-{4-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-phenylsulfanyl}-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine;{2-[4-(2-Methylamino-acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2Hpyrazol-3-yl)-amine;[2-(4-Acetamidophenylsulfanyl)-8-fluoro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;and (1H-Indazol-3-yl)-(2-phenylsulfanyl-quinazolin-4-yl)-amine.
 9. Acomposition comprising a compound according to any one of claims 1-8,and a pharmaceutically acceptable carrier.
 10. The composition accordingto claim 9, further comprising an additional therapeutic agent.
 11. Thecomposition according to claim 9, wherein said composition is formulatedfor administration to a human.
 12. A method of inhibiting Aurora-2,GSK-3, CDK-2, or Src activity in a biological sample comprising the stepof contacting said biological sample with a compound according to anyone of claims 1-8.
 13. A method of inhibiting Aurora-2 activity in apatient comprising the step of administering to said patient acomposition according to claim
 9. 14. A method of inhibiting Aurora-2activity in a patient comprising the step of administering to saidpatient a composition according to claim
 10. 15. A method of treating anAurora-2-mediated disease, which method comprises administering to apatient in need of such a treatment a therapeutically effective amountof a composition according to claim
 9. 16. The method according to claim15, wherein said disease is selected from colon, breast, stomach, orovarian cancer.
 17. The method according to claim 16, wherein saidmethod further comprises administering an additional therapeutic agent.18. The method according to claim 17, wherein said additionaltherapeutic agent is a chemotherapeutic agent.
 19. A method ofinhibiting GSK-3 in a patient comprising the step of administering tosaid patient a composition according to claim
 9. 20. A method ofinhibiting GSK-3 activity in a patient comprising the step ofadministering to said patient a composition according to claim
 10. 21. Amethod of method of treating a GSK-3-mediated disease, which methodcomprises administering to a patient in need of such a treatment atherapeutically effective amount of a composition according to claim 9.22. The method according to claim 20, wherein said GSK-3-mediateddisease is selected from diabetes, Alzheimer's disease, Huntington'sDisease, Parkinson's Disease, AIDS-associated dementia, amyotrophiclateral sclerosis (AML), multiple sclerosis (MS), schizophrenia,cardiomycete hypertrophy, reperfusion/ischemia, or baldness.
 23. Themethod according to claim 21, wherein said GSK-3-mediated disease isdiabetes.
 24. A method of enhancing glycogen synthesis or lowering bloodlevels of glucose in a patient in need thereof, which method comprisesadministering to said patient a therapeutically effective amount of acomposition according to claim
 9. 25. A method of inhibiting theproduction of hyperphosphorylated Tau protein in a patient, which methodcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a composition according to claim
 9. 26. A method ofinhibiting the phosphorylation of β-catenin, which method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a composition according to claim
 9. 27. A method of inhibitingCDK-2 activity in a patient comprising the step of administering to saidpatient a composition according to claim
 9. 28. A method of method oftreating CDK-2-mediated disease, which method comprises administering toa patient in need of such a treatment a therapeutically effective amountof a composition according to claim
 9. 29. A method of inhibiting Srcactivity in a patient comprising the step of administering to saidpatient a composition according to claim
 9. 30. A method of treating aSrc-mediated disease, which method comprises administering to a patientin need of such a treatment a therapeutically effective amount of acomposition according to claim 9.